Apparatus and methods for delivering devices for reducing left atrial pressure

ABSTRACT

A device for regulating blood pressure between a patient&#39;s left atrium and right atrium, and apparatus for delivery the device, are provided. The delivery apparatus may include one or more latching legs, a release ring, a pull chord, and a catheter wherein the latching legs are configured to engage the device for delivery. The inventive devices may reduce left atrial pressure and left ventricular end diastolic pressure, and may increase cardiac output, increase ejection fraction, relieve pulmonary congestion, and lower pulmonary artery pressure, among other benefits. The inventive devices may be used, for example, to treat subjects having heart failure, pulmonary congestion, or myocardial infarction, among other pathologies.

I. CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation patent application of U.S. patentapplication Ser. No. 15/656,936, filed Jul. 21, 2017, now U.S. Pat. No.10,478,594, which is a continuation of U.S. patent application Ser. No.14/282,615, filed May 20, 2014, now U.S. Pat. No. 9,713,696, whichclaims the benefit of priority to U.S. Provisional Application Ser. No.61/825,931, filed May 21, 2013, the contents of each of which areincorporated herein by reference in their entirety.

II. FIELD OF THE INVENTION

This application generally relates to devices and methods for reducingleft atrial pressure, particularly in subjects with heart pathologiessuch as congestive heart failure (CHF) or myocardial infarction (MI),and apparatus for delivering such devices.

III. BACKGROUND OF THE INVENTION

Heart failure is the physiological state in which cardiac output isinsufficient to meet the needs of the body and the lungs. CHF occurswhen cardiac output is relatively low and the body becomes congestedwith fluid. There are many possible underlying causes of CHF, includingmyocardial infarction, coronary artery disease, valvular disease, andmyocarditis. Chronic heart failure is associated with neurohormonalactivation and alterations in autonomic control. Although thesecompensatory neurohormonal mechanisms provide valuable support for theheart under normal physiological circumstances, they also have afundamental role in the development and subsequent progression of CHF.For example, one of the body's main compensatory mechanisms for reducedblood flow in CHF is to increase the amount of salt and water retainedby the kidneys. Retaining salt and water, instead of excreting it intothe urine, increases the volume of blood in the bloodstream and helps tomaintain blood pressure. However, the larger volume of blood alsostretches the heart muscle, enlarging the heart chambers, particularlythe ventricles. At a certain amount of stretching, the heart'scontractions become weakened, and the heart failure worsens. Anothercompensatory mechanism is vasoconstriction of the arterial system. Thismechanism, like salt and water retention, raises the blood pressure tohelp maintain adequate perfusion.

In low ejection fraction (EF) heart failure, high pressures in the heartresult from the body's attempt to maintain the high pressures needed foradequate peripheral perfusion. However, the heart weakens as a result ofthe high pressures, aggravating the disorder. Pressure in the leftatrium may exceed 25 mmHg, at which stage, fluids from the blood flowingthrough the pulmonary circulatory system flow out of the interstitialspaces and into the alveoli, causing pulmonary edema and lungcongestion.

Table 1 lists typical ranges of right atrial pressure (RAP), rightventricular pressure (RVP), left atrial pressure (LAP), left ventricularpressure (LVP), cardiac output (CO), and stroke volume (SV) for a normalheart and for a heart suffering from CHF. In a normal heart beating ataround 70 beats/minute, the stroke volume needed to maintain normalcardiac output is about 60 to 100 milliliters. When the preload,after-load, and contractility of the heart are normal, the pressuresrequired to achieve normal cardiac output are listed in Table 1. In aheart suffering from CHF, the hemodynamic parameters change (as shown inTable 1) to maximize peripheral perfusion.

TABLE 1 Parameter Normal Range CHF Range RAP (mmHg)  2-6    6-15  RVP(mmHg) 15-25  20-40  LAP (mmHg)  6-12  15-30  LVP (mmHg)  6-120 20-220CO (liters/minute)  4-8    2-6   SV (milliliters/beat) 60-100 30-80 

CHF is generally classified as either systolic heart failure (SHF) ordiastolic heart failure (DHF). In SHF, the pumping action of the heartis reduced or weakened. A common clinical measurement is the ejectionfraction, which is a function of the blood ejected out of the leftventricle (stroke volume), divided by the maximum volume remaining inthe left ventricle at the end of diastole or relaxation phase. A normalejection fraction is greater than 50%. Systolic heart failure has adecreased ejection fraction of less than 50%. A patient with SHF mayusually have a larger left ventricle because of a phenomenon calledcardiac remodeling that occurs secondarily to the higher ventricularpressures.

In DHF, the heart generally contracts normally, with a normal ejectionfraction, but is stiffer, or less compliant, than a healthy heart wouldbe when relaxing and filling with blood. This stiffness may impede bloodfrom filling the heart, and produce backup into the lungs, which mayresult in pulmonary venous hypertension and lung edema. DHF is morecommon in patients older than 75 years, especially in women with highblood pressure.

Both variants of CHF have been treated using pharmacological approaches,which typically involve the use of vasodilators for reducing theworkload of the heart by reducing systemic vascular resistance, as wellas diuretics, which inhibit fluid accumulation and edema formation, andreduce cardiac filling pressure.

In more severe cases of CHF, assist devices such as mechanical pumpshave been used to reduce the load on the heart by performing all or partof the pumping function normally done by the heart. Chronic leftventricular assist devices (LVAD), and cardiac transplantation, oftenare used as measures of last resort. However, such assist devices aretypically intended to improve the pumping capacity of the heart, toincrease cardiac output to levels compatible with normal life, and tosustain the patient until a donor heart for transplantation becomesavailable. Such mechanical devices enable propulsion of significantvolumes of blood (liters/min), but are limited by a need for a powersupply, relatively large pumps, and the risk of hemolysis, thrombusformation, and infection. Temporary assist devices, intra-aorticballoons, and pacing devices have also been used.

In addition to cardiac transplant, which is highly invasive and limitedby the ability of donor hearts, surgical approaches such as dynamiccardiomyoplastic or the Batista partial left ventriculectomy may also beused in severe cases.

Various devices have been developed using stents or conduits to modifyblood pressure and flow within a given vessel, or between chambers ofthe heart. For example, U.S. Pat. No. 6,120,534 to Ruiz is directed toan endoluminal stent for regulating the flow of fluids through a bodyvessel or organ, for example for regulating blood flow through thepulmonary artery to treat congenital heart defects. The stent mayinclude an expandable mesh having lobed or conical portions joined by aconstricted region, which limits flow through the stent. The mesh maycomprise longitudinal struts connected by transverse sinusoidal orserpentine connecting members. Ruiz is silent on the treatment of CHF orthe reduction of left atrial pressure.

U.S. Pat. No. 6,468,303 to Amplatz et al. discloses a collapsiblemedical device and associated method for shunting selected organs andvessels. Amplatz discloses that the device may be suitable to shunt aseptal defect of a patient's heart, for example, by creating a shunt inthe atrial septum of a neonate with hypoplastic left heart syndrome(HLHS). Amplatz discloses that increasing mixing of pulmonary andsystemic venous blood improves oxygen saturation. Amplatz discloses thatdepending on the hemodynamics, the shunting passage can later be closedby an occluding device. Amplatz is silent on the treatment of CHF or thereduction of left atrial pressure, as well as on means for regulatingthe rate of blood flow through the device.

U.S. Patent Publication No. 2005/0165344 to Dobak, III discloses anapparatus for treating heart failure that includes a conduit positionedin a hole in the atrial septum of the heart, to allow flow from the leftatrium into the right atrium. Dobak discloses that the shunting of bloodwill reduce left atrial pressures, thereby preventing pulmonary edemaand progressive left ventricular dysfunction, and reducing LVEDP. Dobakdiscloses that the conduit may include a self-expandable tube withretention struts, such as metallic arms that exert a slight force on theatrial septum on both sides and pinch or clamp the valve to the septum,and a one-way valve member, such as a tilting disk, bileaflet design, ora flap valve formed of fixed animal pericardial tissue. However, Dobakstates that a valved design may not be optimal due to a risk of bloodstasis and thrombus formation on the valve, and that valves can alsodamage blood components due to turbulent flow effects. Dobak does notprovide any specific guidance on how to avoid such problems.

In view of the foregoing, it would be desirable to provide devices forreducing left atrial pressure, and apparatus for delivering such devicesto the atrial septum of the heart.

IV. SUMMARY OF THE INVENTION

The present invention overcomes the drawbacks of previously-knowndevices by providing apparatus for delivering a device for regulatingblood pressure between a patient's left atrium and right atrium. Theapparatus may include one or more latching legs, a release ring, a pullchord, a spring, and a catheter. The one or more latching legs may havea hook portion and may be configured to move from a first position,where the one or more latching legs extend radially outward, to a secondposition, where the one or more latching legs move radially inward torelease the device. The pull chord may be configured to move the one ormore latching legs from the first position to the second position. Thecatheter has a lumen and a center axis and the one or more latching legsand the pull chord may be at least partially disposed within the lumen.The hook portion of at least one of the one or more latching legs mayhook outwardly away from the center axis to permit the latching legs toengage the device at the inner surface of the device.

At least one of the latching legs may include a ramp portion disposedproximal to the hook portion. The release ring may be coupled to the oneor more latching legs and configured to contact an inner section of theramp portion in the first position and to contact an outer section ofthe ramp portion in the second position. The pull chord may be coupledto the release ring such that actuation of the pull chord moves therelease ring from the first position, where the one or more latchinglegs extend radially outward, to the second position, where the one ormore latching legs move radially inward to release the device.

The apparatus may include a sheath and the catheter may be configured tobe at least partially disposed within the sheath. The device may beconfigured to be disposed within the sheath in a contracted, deliverystate. The one or more latching legs may be configured to move thedevice longitudinally forward and longitudinally backward through thesheath. Preferably, the apparatus is configured to deliver the device toan atrial septum of the patient.

In addition, the apparatus may include a handle coupled to the pullchord and disposed at a proximal end of the catheter, wherein the pullchord is actuated via the handle. A release ring base may be coupled tothe release ring and the pull chord and the pull chord may move therelease ring base to move the release ring from the first position thesecond position. A spring may be coupled to the release ring base, andthe spring may be configured to bias the release ring towards the firstposition. In addition, the spring may be configured to limit travel ofthe release ring by reaching full compression. The apparatus also mayinclude an annular member disposed proximal to release ring base andconfigured to maintain the spring between the release ring base and theannular member.

The one or more latching legs may include two latching legs that share acommon ramp portion and a third latching leg having a separate rampportion. The catheter may include a catheter end having an end lumenextending therethrough, and the one or more latching legs, the releasering, and the pull chord may be at least partially disposed within theend lumen.

In accordance with one aspect of the present invention, a method ofdelivering a device to a subject with heart pathology is provided. Themethod may include providing a delivery apparatus comprising one or morelatching legs having a hook portion and a catheter having a lumen and acenter axis, the one or more latching legs at least partially disposedwithin the lumen and the hook portion of the one or more latching legsconfigured to hook outwardly away from the center axis; coupling thehook portion to the device; positioning the device across a puncturethrough the fossa ovalis; and moving the one or more latching legs froma first position, where the one or more latching legs extend radiallyoutward, to a second position, where the one or more latching legs moveradially inward to decouple the hook portion from the device such thatthe device engages the atrial septum.

The method may include inserting the device in a sheath, partiallyretracting the sheath such that the device engages the left side of theatrial septum, and then fully retracting the sheath such that the deviceis partially disposed in the right atrium. The device may have first andsecond flared end regions and a neck region disposed therebetween, andoptionally a tissue valve. The first flared end region may be disposedin, and engage, the atrial septum, and the second flared end region maybe disposed in, and flank, the atrial septum.

The one or more latching legs may include a ramp portion disposedproximal to the hook portion and the delivery apparatus furthercomprises a release ring coupled to the one or more latching legs. Insuch an embodiment, moving the one or more latching legs furtherincludes moving the release ring, via a pull chord, from the firstposition, where the release ring contacts an inner section of the rampportion, to the second position, where the release ring contacts anouter section of the ramp portion.

Positioning the device may include positioning the device across thepuncture through the fossa ovalis such that the neck region ispositioned in the puncture. The method may include identifying themiddle of the fossa ovalis of the atrial septum by pressing a needleagainst the fossa ovalis to partially tent the fossa ovalis, andpuncturing the middle of the fossa ovalis with the needle. The puncturemay be through the middle of the fossa ovalis and the device may bedeployed away from the limbus, atrial wall, and the ridge between theinferior vena cava and coronary sinus.

In accordance with another aspect of the present invention, a method ofdelivering a device to a subject with heart pathology is provided. Themethod may include providing a delivery apparatus comprising one or morelatching legs having a hook portion and a catheter having a lumen and acenter axis, the one or more latching legs at least partially disposedwithin the lumen; coupling the hook portion to the device; positioningthe device across a puncture through the fossa ovalis at anon-perpendicular angle between the center axis of the catheter and anouter wall of the atrial septum; and moving the one or more latchinglegs from a first position, where the one or more latching legs extendradially outward, to a second position, where the one or more latchinglegs move radially inward to decouple the hook portion from the devicesuch that the device engages the atrial septum.

Embodiments of the present invention also provide hourglass-shapeddevices for reducing left atrial pressure, and methods of making andusing the same. As elaborated further herein, such reductions in leftatrial pressure may increase cardiac output, relieve pulmonarycongestion, and lower pulmonary artery pressure, among other benefits.The inventive devices are configured for implantation through the atrialseptum, and particularly through the middle of the fossa ovalis, awayfrom the surrounding limbus, inferior vena cava (IVC), and atrial wall.The devices are configured to provide one-way blood flow from the leftatrium to the right atrium when the pressure in the left atrium exceedsthe pressure in the right atrium, and thus decompress the left atrium.Such a lowering of left atrial pressure may offset abnormal hemodynamicsassociated with CHF, for example, to reduce congestion as well as theoccurrence of acute cardiogenic pulmonary edema (ACPE), which is asevere manifestation of CHF in which fluid leaks from pulmonarycapillaries into the interstitium and alveoli of the lung. Inparticular, lowering the left atrial pressure may improve the cardiacfunction by:

(1) Decreasing the overall pulmonary circulation pressure, thusdecreasing the afterload on the heart,

(2) Increasing cardiac output by reducing left ventricular end systolicdimensions, and

(3) Reducing the left ventricular end-diastolic pressure (LVEDP) andpulmonary artery pressure (PAP), which in turn may enable the heart towork more efficiently and over time increase cardiac output. Forexample, the oxygen uptake of the myocardium may be reduced, creating amore efficient working point for the myocardium.

As described in further detail below, the devices provided hereincomprise an hourglass or “diabolo” shaped stent encapsulated with abiocompatible material, and optionally secured (e.g., sutured) to atissue valve. The stent, which may be formed of shape memory material,for example a shape memory metal such as NiTi, comprises a neck regiondisposed between two flared end regions. The tissue valve is coupled toa flared end region configured for implantation in the right atrium.Specifically, the device may be implanted by forming a puncture throughthe atrial septum, particularly through the fossa ovalis, and thenpercutaneously inserting the device therethrough such that the necklodges in the puncture, the flared end to which the tissue valve iscoupled engages the right side of the atrial septum, and the otherflared end flanks the left side of the atrial septum (e.g., is spacedapart from and does not contact the left side of the atrial septum).Placement in the middle of the fossa ovalis is useful because theengagement of the right-side flared end with the atrial septum enhancesthe stability of the valve. The neck region and the flared end regionfor placement in the left atrium may each be covered with abiocompatible polymer, such as expanded polytetrafluoroethylene (ePTFE),polyurethane, DACRON (polyethylene terephthalate), silicone,polycarbonate urethane, or pericardial tissue from an equine, bovine, orporcine source, which is optionally treated so as to promote a limitedamount of tissue ingrowth, e.g., of epithelial tissue or a neointimalayer. The tissue valve is connected to the biocompatible polymer in theright-side flared end region, close to the neck region, and ispreferably a tricuspid, bicuspid, or duckbill valve configured to allowblood to flow from the left atrium to the right atrium when the pressurein the left atrium exceeds that in the right atrium, but prevent flowfrom the right atrium to the left atrium. In preferred embodiments, thedevice is effective to maintain the pressure differential between theleft atrium and right atrium to 15 mmHg or less.

Under one aspect of the present invention, a device for regulating bloodpressure between a patient's left atrium and right atrium comprises anhourglass-shaped stent comprising a neck and first and second flared endregions, the neck disposed between the first and second end regions andconfigured to engage the fossa ovalis of the patient's atrial septum;and optionally a one-way tissue valve coupled to the first flared endregion and configured to shunt blood from the left atrium to the rightatrium when blood pressure in the left atrium exceeds blood pressure inthe right atrium. In accordance with one aspect of the invention, movingportions of the valve are disposed in the right atrium, joined to butspaced apart from the neck region.

The hourglass-shaped stent may include a shape memory material (e.g.,metal) coated with a biocompatible polymer from a portion of the firstflared end region, through the neck region, and through the secondflared end region, and the tissue valve may extend between the firstflared end region and the biocompatible polymer. Providing the tissuevalve in the side of the device to be implanted in the right atrium(that is, in the first flared end region) may inhibit thrombus formationand tissue ingrowth by providing that the tissue valve, as well as theregion where the tissue valve is secured (e.g., sutured) to thebiocompatible polymer, is continuously flushed with blood flowingthrough the right atrium. By comparison, if the tissue valve was insteadsecured (e.g., sutured) to the biocompatible polymer in the neck region,then the interface between the two would contact the tissue of the fossaovalis, which potentially would encourage excessive tissue ingrowth,create leakages, and cause inflammation. Moreover, tissue ingrowth intothe neck region would cause a step in the flow of blood in the narrowestpart of the device, where flow is fastest, which would increase shearstresses and cause coagulation. Instead providing the tissue valveentirely within the right atrial side of the device inhibits contactbetween the tissue valve and the tissue of the atrial septum and fossaovalis. Further, any tissue that ingrows into the valve will notsubstantially affect blood flow through the device, because the valve islocated in a portion of the device having a significantly largerdiameter than the neck region. Moreover, if the biocompatible tissuewere instead to continue on the portions of the frame positioned overthe tissue valve, it may create locations of blood stasis between theleaflets of the tissue valve and the biocompatible material. Having thevalve entirely on the right atrial side and without biocompatiblematerial on the overlying frame enables continuous flushing of theexternal sides of the tissue valve with blood circulating in the rightatrium.

The biocompatible material preferably promotes limited (or inhibitsexcessive) tissue ingrowth into the valve, the tissue ingrowth includingan endothelial layer or neointima layer inhibiting thrombogenicity ofthe device. The endothelial or neointima layer may grow to a thicknessof 0.2 mm or less, so as to render the material inert and inhibithyperplasia.

The hourglass-shaped stent may include a plurality of sinusoidal ringsinterconnected by longitudinally extending struts. In some embodiments,when the shunt is deployed across the patient's atrial septum, the firstflared end region protrudes 5.5 to 7.5 mm into the right atrium. Thesecond flared end region may protrude 2.5 to 7 mm into the left atrium.The neck may have a diameter of 4.5 to 5.5 mm. The first flared endregion may have a diameter between 9 and 13 mm, and the second flaredend region may have a diameter between 8 and 15 mm. The first and secondflared end regions each may flare by about 50 to 120 degrees. Forexample, in one embodiment, the first flared end region flares by about80 degrees, that is, the steepest part of the outer surface of the firstflared end region is at an angle of approximately 40 degrees relative toa central longitudinal axis of the device. The second flared end regionmay flare by about 30-70 degrees, where the steepest part of the outersurface of the second flared end region may be at an angle ofapproximately 35 degrees relative to the central longitudinal axis ofthe device. The second flare may be have a tapered shape starting with awider angle in the range of about 50-70 degrees and ending with a narrowangle in the range of about 30-40 degrees.

The inlet of the tissue valve may be about 1-3 mm from a narrowestportion of the neck region, and the outlet of the tissue valve may beabout 5-8 mm from the narrowest portion of the neck region. The tissuevalve may comprise a sheet of tissue having a flattened length of about10-16 mm, and the sheet of tissue may be folded and sutured so as todefine two or more leaflets each having a length of about 5-8 mm. Forexample, the tissue sheet may have a flattened length of no greater than18 mm, for example, a length of 10-16 mm, or 12-14 mm, or 14-18 mm, andmay be folded and sutured to define two or more leaflets each having alength of, for example, 9 mm or less, or 8 mm or less, or 7 mm or less,or 6 mm or less, or even 5 mm or less, e.g., 5-8 mm. The tissue sheetmay have a flattened height no greater than 10 mm, for example, a heightof 2-10 mm, or 4-10 mm, or 4-8 mm, or 6-8 mm, or 4-6 mm. The tissuesheet may have a flattened area of no greater than 150 square mm, forexample, 60-150 square mm, or 80-120 square mm, or 100-140 square mm, or60-100 square mm.

The hourglass-shaped stent may be configured to transition between acollapsed state suitable for percutaneous delivery and an expanded statewhen deployed across the patient's fossa ovalis. The stent may have anhourglass configuration in the expanded state. The hourglassconfiguration may be asymmetric. The stent may be configured forimplantation through the middle of the fossa ovalis, away from thesurrounding limbus, inferior vena cava, and atrial wall. Thehourglass-shaped stent may be designed in such way that when collapsedinto a sheath, the neck of the stent maintains a diameter smaller thanthe sheath inner diameter. The sheath may have a tapered tip withlocally reduced diameter at its tip. The neck of the stent is configuredto self-position itself within the sheath tip when the stent ispartially deployed. Additionally, when the stent is partially deployed,a relatively high force is required to further advance the stent intothe left atrium. Such additional force provides confirmation to theclinician that the stent is partially deployed, reduces the chance oftotal deployment in the left atrium, and reduces the risk that emboliwill travel into the left atrium during full deployment.

The one-way tissue valve may have two or more leaflets, e.g., may have atricuspid or bicuspid design. The one-way tissue valve may comprisepericardial tissue, which in one embodiment may consist primarily of themesothelial and loose connective tissue layers, and substantially nodense fibrous layer. Note that the dimensions of the hourglass-shapeddevice may be significantly smaller than those of replacement aorticvalves, which may for example have a diameter of 23 mm and require theuse of larger, thicker valve leaflets to maintain the higher stressesgenerated by the combination of higher pressures and larger diameters.By comparison, the inventive device has much smaller dimensions,allowing the use of thinner tissue (e.g., about one third the thicknessof tissue used in a replacement aortic valve), for example, pericardialtissue in which the external dense fibrous layer is delaminated and themesothelial and loose connective tissue is retained.

Under another aspect of the present invention, a device for regulatingblood pressure between a patient's left atrium and right atrium includesa stent comprising a neck region and first and second flared endregions, the neck region disposed between the first and second endregions and configured to engage the fossa ovalis of the patient'satrial septum; a biocompatible material disposed on the stent in theneck and the second flared end region and a portion of the first flaredend region; and optionally a one-way tissue valve configured to shuntblood from the left atrium to the right atrium when blood pressure inthe left atrium exceeds blood pressure in the right atrium, the valvehaving an outlet coupled to the first flared end region and an inletcoupled to an edge of the biocompatible material, the valve and thebiocompatible material defining a continuous sheath that inhibitsexcessive tissue ingrowth into the valve and channels blood flow throughthe valve. In one embodiment, the edge of the biocompatible material isabout 1-3 mm, e.g., 2 mm, from a narrowest portion of the neck region.

Under another aspect, a method of treating a subject with heartpathology comprises: providing a device having first and second flaredend regions and a neck region disposed therebetween, and a tissue valvecoupled to the first flared end region; deploying the device across apuncture through the subject's fossa ovalis such that the neck region ispositioned in the puncture, the first flared end region is disposed in,and engages, the atrial septum, and the second flared end region isdisposed in, and flanks, the atrial septum; and reducing left atrialpressure and left ventricular end diastolic pressure by shunting bloodfrom the left atrium to the right atrium through the device when theleft atrial pressure exceeds the right atrial pressure.

Subjects with a variety of heart pathologies may be treated with, andmay benefit from, the inventive device. For example, subjects withmyocardial infarction may be treated, for example by deploying thedevice during a period immediately following the myocardial infarction,e.g., within six months after the myocardial infarction, or within twoweeks following the myocardial infarction. Other heart pathologies thatmay be treated include heart failure and pulmonary congestion. Reducingthe left atrial pressure and left ventricular end diastolic pressure mayprovide a variety of benefits, including but not limited to increasingcardiac output; decreasing pulmonary congestion; decreasing pulmonaryartery pressure; increasing ejection fraction; increasing fractionalshortening; and decreasing left ventricle internal diameter in systole.Means may be provided for measuring such parameters.

Such methods may include identifying the middle of the fossa ovalis ofthe atrial septum by pressing a needle against the fossa ovalis topartially tent the fossa ovalis; and puncturing the middle of the fossaovalis with the needle.

Under yet another aspect of the present invention, a method of making adevice comprises: providing a tube of shape-memory metal; expanding thetube on a mandrel to define first and second flared end regions and aneck therebetween, and heating the expanded tube to set the shape;coating the neck and second flared end region with a biocompatiblematerial; providing a valve of animal pericardial tissue having leafletsfixed in a normally closed position; and securing an inlet of the valveto the first flared end region and to the biocompatible polymer at theneck region. The tube may be laser cut and may include a plurality ofsinusoidal rings connected by longitudinally extending struts, and thevalve may be sutured to the struts and to the biocompatible material toform a passage for blood.

V. BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D illustrate perspective views of an hourglass-shaped devicehaving a tricuspid valve, according to some embodiments of the presentinvention.

FIG. 2A schematically illustrates a plan view of the right atrial sideof the atrial septum, including a site for implanting anhourglass-shaped device through the middle of the fossa ovalis.

FIG. 2B schematically illustrates a cross-sectional view of thehourglass-shaped device of FIGS. 1A-1D positioned in the fossa ovalis ofthe atrial septum, according to some embodiments of the presentinvention.

FIG. 3A is a flow chart of steps in a method of making anhourglass-shaped device, according to some embodiments of the presentinvention.

FIGS. 3B-3E illustrate plan views of sheets of material for use inpreparing tissue valves, according to some embodiments of the presentinvention.

FIG. 4 is a flow chart of steps in a method of percutaneously implantingan hourglass-shaped device in a puncture through the fossa ovalis,according to some embodiments of the present invention.

FIGS. 5A-5D schematically illustrate steps taken during the method ofFIG. 4, according to some embodiments of the present invention.

FIG. 6A is an image from a computational fluid dynamic model of flowthrough an hourglass-shaped device in the open configuration.

FIG. 6B is a plot showing the relationship between the left-to-rightatrial pressure differential and the flow rate through the valve forhourglass-shaped devices having different valve diameters, according tosome embodiments of the present invention.

FIG. 7 is a flow chart of steps in a method of noninvasively determiningleft atrial pressure using an hourglass-shaped device, and adjusting atreatment plan based on same, according to some embodiments of thepresent invention.

FIGS. 8A-8C illustrate perspective views of an alternativehourglass-shaped device, according to some embodiments of the presentinvention.

FIG. 9 is a perspective view of a further alternative hourglass-shapeddevice, according to some embodiments of the present invention.

FIGS. 10A-10D are plots respectively showing the left atrial pressure,right atrial pressure, ejection fraction, and pulmonary artery pressurein animals into which an exemplary hourglass-shaped device wasimplanted, as well as control animals, during a twelve-week study.

FIGS. 11A-11B are photographic images showing an hourglass-shaped devicefollowing explantation from an animal after being implanted for 12weeks.

FIG. 11C is a microscope image of a cross-section of an hourglass-shapeddevice following explantation from an animal after being implanted for12 weeks.

FIGS. 12A and 12B illustrate an exemplary apparatus for deliveringdevices in accordance with the present invention, wherein the exemplaryapparatus is in the engaged position in FIG. 12A and the disengagedposition in FIG. 12B.

FIGS. 13A and 13B, respectively, illustrate the distal end of theexemplary apparatus in the engaged position shown in FIG. 12A and thedisengaged position shown in FIG. 12B.

FIGS. 14A to 14D illustrate the inner components at the distal end ofthe exemplary apparatus, wherein FIGS. 14A and 14C show the componentsin the engaged position and FIGS. 14B and 14D show the components in thedisengaged position.

FIG. 15A illustrates the distal end of an exemplary delivery apparatusengaged to an exemplary device, partially shown, in accordance with thepresent invention and FIG. 15B illustrates the exemplary deliveryapparatus disengaged from the exemplary device.

FIG. 16 is a flow chart of steps in a method of percutaneouslyimplanting an hourglass-shaped device in a puncture through the fossaovalis using exemplary delivery apparatus, according to some embodimentsof the present invention.

FIGS. 17A-17Q schematically illustrate steps taken during the method ofFIG. 16, according to some embodiments of the present invention

VI. DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention are directed to devices that reduceleft atrial pressure, and thus may be useful in treating subjectssuffering from congestive heart failure (CHF) or other disordersassociated with elevated left atrial pressure. Specifically, theinventive device includes an hourglass or “diabolo” shaped stent,preferably formed of a shape memory metal, and, optionally, abiocompatible valve coupled thereto. The stent is configured to lodgesecurely in the atrial septum, preferably the fossa ovalis, and to allowblood flow from the left atrium to the right atrium, preferably throughthe fossa ovalis, and the valve may be used to allow one-way blood flowwhen blood pressure in the left atrium exceeds that on the right.Usefully, the inventive devices are configured so as to reduce bloodpressure in the left atrium even when the pressure differentialtherebetween is relatively low; to provide a smooth flow path with alarge opening, thus inhibiting turbulence and high shear stresses thatwould otherwise promote thrombus formation; to seal securely with rapidvalve closure when the left and right atrial pressures equalize or theright atrial pressure exceeds left atrial pressure; and to have arelatively small implantation footprint so as to inhibit tissueovergrowth and inflammatory response.

First, a preferred embodiment of the inventive hourglass-shaped devicewill be described, and then methods of making, implanting, and using thesame will be described. Then, the hemodynamic flow characteristics ofsome illustrative devices will be described, as well as a method forusing an hourglass-shaped device to noninvasively determine left atrialpressure based on images of blood flowing through the implanted device.Some alternative embodiments will then be described. An Example will beprovided that describes a study performed on several animals into whichan exemplary device was implanted, as compared to a group of controlanimals. Apparatus for delivering the devices of the present inventionalso will be described.

FIGS. 1A-1D illustrate perspective views of an illustrative embodimentof the inventive device. First, with reference to FIG. 1A, device 100includes an hourglass-shaped stent 110 and optional tissue valve 130,illustratively, a tricuspid valve including three coapting leaflets.Device 100 has three general regions: first flared or funnel-shaped endregion 102, second flared or funnel-shaped end region 106, and neckregion 104 disposed between the first and second flared end regions.Neck region 104 is configured to lodge in a puncture formed in theatrial septum, preferably in the fossa ovalis, using methods describedin greater detail below. First flared end region 102 is configured toengage the right side of the atrial septum, and second flared end region106 is configured to flank the left side of the atrial septum, whenimplanted. The particular dimensions and configurations of neck region104 and first and second flared end regions 102, 106 may be selected soas to inhibit the formation of eddy currents when implanted, and thusinhibit thrombus formation; to inhibit tissue ingrowth in selectedregions; to promote tissue ingrowth in other selected regions; and toprovide a desirable rate of blood flow between the left and right atria.

Hourglass-shaped stent 110 is preferably formed of a shape memory metal,e.g., NITINOL, or any other suitable material known in the art. Stent110 includes a plurality of sinusoidal rings 112-116 interconnected bylongitudinally extending struts 111. Rings 112-116 and struts 111 may beof unitary construction, that is, entire stent 110 may be laser cut froma tube of shape memory metal. As can be seen in FIG. 1A, neck region 104and second flared end region 106 are covered with biocompatible material120, for example a sheet of a polymer such as expandedpolytetrafluoroethylene (ePTFE), silicone, polycarbonate urethane,DACRON (polyethylene terephthalate), or polyurethane, or of a naturalmaterial such as pericardial tissue, e.g., from an equine, bovine, orporcine source. Specifically, the region extending approximately fromsinusoidal ring 113 to sinusoidal ring 116 is covered with biocompatiblematerial 120. Material 120 preferably is generally smooth so as toinhibit thrombus formation, and optionally may be impregnated withcarbon so as to promote tissue ingrowth. Preferably, portions of stent110 associated with first flared end region 102 are not covered with thebiocompatible material, but are left as bare metal, so as to inhibit theformation of stagnant flow regions in the right atrium that otherwiseand to provide substantially free blood flow around leaflets 131, so asto inhibit significant tissue growth on leaflets 131. The bare metalregions of stent 110, as well as any other regions of the stent,optionally may be electropolished or otherwise treated so as to inhibitthrombus formation, using any suitable method known in the art.

An inlet end of tissue valve 130 is coupled to stent 110 in first flaredend region 102. In the illustrated embodiment, tissue valve 130 is atricuspid valve that includes first, second, and third leaflets 131defining valve opening 132. Other embodiments, illustrated furtherbelow, may include a bicuspid or duckbill valve, or other suitable valveconstruction. However, it is believed that tricuspid valves may provideenhanced leaflet coaptation as compared to other valve types, such thateven if the tissue valve stiffens as a result of tissue ingrowthfollowing implantation, there may still be sufficient leaflet materialto provide coaptation with the other leaflets and close the valve.Preferably, tissue valve 130 opens at a pressure of less than 1 mm Hg,closes at a pressure gradient of between 0-0.5 mm Hg, and remains closedat relatively high back pressures, for example at back pressures of atleast 40 mm Hg. Tissue valve 130 may be formed using any natural orsynthetic biocompatible material, including but not limited topericardial tissue, e.g., bovine, equine, or porcine tissue, or asuitable polymer. Pericardial tissue, and in particular bovinepericardial tissue, is preferred because of its strength and durability.The pericardial tissue may be thinned to enhance compliance, for exampleas described in greater detail below, and may be fixed using anysuitable method, for example, using glutaraldehyde or otherbiocompatible fixative.

As shown in FIG. 1B, tissue valve 130 is coupled, e.g., sutured, tofirst, second, and third longitudinally extending struts 111′, 111″, and111′″ in the region extending between first (uppermost) sinusoidal ring112 and second sinusoidal ring 113. Referring to FIGS. 1A and 1D, tissuevalve 130 is also coupled to the upper edge of biocompatible material120, at or near sinusoidal ring 113, for example along line 121 asshown. As such, tissue valve 130 and biocompatible material 120 togetherprovide a smooth profile to guide blood flow from the left atrium to theright atrium, that is, from the second flared end region 106, throughneck region 104, and through first flared end region 102. In accordancewith one aspect of the invention, the inlet to tissue valve 130 isanchored to neck region 104, such that leaflets 131 extend into theright atrium. In this manner, any eccentricities that may arise from theout-of-roundness of the puncture through the fossa ovalis duringimplantation will not be transferred to the free ends of leaflets 131,thus reducing the risk that any eccentricity of the stent in neck region104 could disturb proper coaptation of the valve leaflets.

FIGS. 1A and 1B illustrate device 100 when tissue valve 130 is in anopen configuration, in which leaflets 131 are in an open position topermit flow, and FIG. 1C illustrates device 100 when tissue valve 130 isin a closed configuration, in which leaflets 131 are in a closedposition to inhibit flow. Tissue valve 130 is configured to open whenthe pressure at second flared end region 106 exceeds that at firstflared end region 102. Preferably, however, tissue valve 130 isconfigured to close and therefore inhibit flow in the oppositedirection, i.e., to inhibit flow from first flared end region 102,through neck region 104, and through second flared end region 104, whenthe pressure at the first flared end region exceeds that of the second.Among other things, such a feature is expected to inhibit passage ofthrombus from the right atrium to the left atrium, which could causestroke or death. Moreover, allowing flow of blood with low oxygenationfrom right to left would further aggravate CHF. Further, tissue valve130 preferably is configured to close and therefore inhibit flow ineither direction when the pressures at the first and second flared endregions are approximately equal. Preferably, tissue valve 130 is sizedand has dynamic characteristics selected to maintain a pressuredifferential between the left and right atria of 15 mm Hg or less.

To achieve such flow effects, as well as reduce complexity of devicefabrication, tissue valve 130 preferably is a tricuspid valve, as isillustrated in FIGS. 1A-1D, but alternatively may be a bicuspid valve,for example a duckbill valve, or a mitral valve, as described here afterwith respect to FIGS. 8A-8C and 9. For example, as described in greaterdetail below with respect to FIGS. 3A-3E, tissue valve 130 may be formedof a single piece of thinned animal pericardial tissue that is suturedalong at least one edge to form an open-ended conical or ovoid tube, andthen three-dimensionally fixed to assume a normally closed position. Theinlet or bottom (narrower) end of the tube may be coupled, e.g.,sutured, to biocompatible material 120 at or near sinusoidal ring 113,and the sides of the tube optionally may be sutured to struts 111′,111″, and 111′″, as illustrated in FIG. 1D (strut 111′ not shown in FIG.1D). In one embodiment, the bottom end of the tube is sutured tobiocompatible material 120 along substantially straight line 121 that isapproximately 2-3 mm to the right of the narrowest portion of neckregion 104. Without wishing to be bound by theory, it is believed thatsuch a location for line 121 may be sufficiently large as to inhibittissue from atrial septum 210 from growing into tissue valve 130. Inanother embodiment (not illustrated), the bottom end of tissue valve 130is secured, e.g., sutured to biocompatible material 120 along a curvethat follows the shape of sinusoidal ring 113. During use, the outlet orupper (wider) end of the tube may open and close based on the pressuredifferential between the inlet and outlet ends, that is, between theleft and right atria when implanted. Other suitable valve configurationsmay include bicuspid valves, duckbill valves, sleeve (windsock) valves,flap valves, and the like.

As noted above, hourglass-shaped device 100 preferably is configured forimplantation through the fossa ovalis of the atrial septum, particularlythrough the middle of the fossa ovalis. As known to those skilled in theart, the fossa ovalis is a thinned portion of the atrial septum causedduring fetal development of the heart, which appears as an indent in theright side of the atrial septum and is surrounded by a thicker portionof the atrial septum. While the atrial septum itself may be severalmillimeters thick and muscular, the fossa ovalis may be onlyapproximately one millimeter thick, and is formed primarily of fibroustissue. Advantageously, because the fossa ovalis comprises predominantlyfibrous tissue, that region of the atrial septum is not expected toundergo significant tension or contraction during the cardiac cycle, andthus should not impose significant radial stresses on stent 110 thatcould lead to stress-induce cracking. In addition, the composition ofthe fossa ovalis as primarily fibrous tissue is expected to avoidexcessive endothelialization after implantation.

In some embodiments of the present invention, hourglass-shaped device100 is asymmetrically shaped to take advantage of the natural featuresof atrial septum 210 near the fossa ovalis, and to provide suitable flowcharacteristics. FIG. 2A illustrates a plan view of the right atrialside of the atrial septum 210, including an implantation site 201through the fossa ovalis 212. Preferably, the implantation site 201 isthrough the middle of the fossa ovalis 212, so that the device may beimplanted at a spaced distance from the surrounding limbus 214, inferiorvena cava (IVC) 216, and atrial wall 210. For example, as illustrated inFIG. 2B, first flared end region 102 is configured to be implanted inright atrium 204 and may be tapered so as to have a more cylindricalshape than does second flared end region 106, which is configured to beimplanted in left atrium 202. The more cylindrical shape of first flaredend region 102 may enhance opening and closing of tissue valve 130,while reducing risk of the tissue valve falling back towards stent 110;may increase the proportion of tissue valve 130 that moves during eachopen-close cycle, and thus inhibit tissue growth on the valve; and mayreduce or inhibit contact between first flared end region 102 and thelimbus 214 of the fossa ovalis 212, that is, between first flared endregion 102 and the prominent margin of the fossa ovalis, while stillanchoring device 100 across atrial septum 210. The more cylindricalshape of first flared end region 102 further may reduce or inhibitcontact between first flared end region 102 and the right atrial wall,as well as the ridge 218 separating the coronary sinus from the inferiorvena cava (IVC) (shown in FIG. 2A but not FIG. 2B). Additionally, insome embodiments the first flared end region 102 substantially does notextend beyond the indent of the fossa ovalis in the right atrium, andtherefore substantially does not restrict blood flow from the IVC 216.

In accordance with one aspect of the invention, device 100 preferably isconfigured so as to avoid imposing significant mechanical forces onatrial septum 210 or atria 202, 204, allowing the septum to naturallydeform as the heart beats. For example, muscular areas of septum 210 maychange by over 20% between systole and diastole. It is believed that anysignificant mechanical constraints on the motion of atrial septum 210 insuch areas would lead to the development of relatively large forcesacting on the septum and/or on atrial tissue that contacts device 100,which potentially would otherwise cause the tissue to have aninflammatory response and hyperplasia, and possibly cause device 100 toeventually lose patency. However, by configuring device 100 so that neckregion may be implanted entirely or predominantly in the fibrous tissueof the fossa ovalis 212, the hourglass shape of device 100 is expectedto be sufficiently stable so as to be retained in the septum, whilereducing mechanical loads on the surrounding atrial septum tissue 210.As noted elsewhere herein, tissue ingrowth from atrial septum 210 inregions 230 may further enhance binding of device 100 to the septum.

Also, for example, as illustrated in FIG. 2B, neck region 104 of device100 is significantly narrower than flared end regions 102, 106,facilitating device 100 to “self-locate” in a puncture through atrialseptum 210, particularly when implanted through the fossa ovalis. Insome embodiments, neck region 104 may have a diameter suitable forimplantation in the fossa ovalis, e.g., that is smaller than the fossaovalis, and that also is selected to inhibit blood flow rates exceedinga predetermined threshold. For example, the smallest diameter of neck104 may be between about 3 and 8 mm, e.g., between about 5 mm and 7 mm,preferably between about 5.5 mm and 6.5 mm. For example, it is believedthat diameters of less than about 4.5 mm may in some circumstances notallow sufficient blood flow through the device to decompress the leftatrium, and may reduce long-term patency of device 100, while diametersof greater than about 5.5 mm may allow too much blood flow. For example,flow rates of greater than 2 liters/minute, or even greater than 1.0liters/minute are believed to potentially lead to right heart failure.

In some embodiments, the length of first flared end region 102 also maybe selected to protrude into the right atrium by a distance R betweenthe narrowest portion of neck region 104 and the end of first flaredregion 102 may be approximately 5.0 to 9.0 mm, for example about 5.5 toabout 7.5 mm, or about 6 to about 7 mm, so as not to significantlyprotrude above the limbus of fossa ovalis 212. Second flared end region106 preferably does not significantly engage the left side of atrialseptum 210, and distance L may be between 2.0 and 8.0 mm, for exampleabout 4 to 7 mm, or about 6.0 mm. It is believed that configuring firstand second flared end regions 102, 106 so as to extend by as short adistance as possible into the right and left atria, respectively, whilestill maintaining satisfactory flow characteristics and stabilization inatrial septum 210, may reduce blockage of flow from the inferior venacava (IVC) in the right atrium and from the pulmonary veins in the leftatrium. In one illustrative embodiment, distance R is about 6.5 mm anddistance L is about 6.0 mm. In some embodiments, the overall dimensionsof device 100 may be 8-20 mm long (L+R, in FIG. 2B), e.g., about 10-15mm, e.g., about 11-14 mm, e.g., about 12.5 mm.

The diameters of the first and second flared end regions further may beselected to stabilize device 100 in the puncture through atrial septum210, e.g., in the puncture through fossa ovalis 212. For example, firstflared end region 102 may have a diameter of 8-15 mm at its widestpoint, e.g., about 10-13 mm or about 11.4 mm; and second flared endregion 106 may have a diameter of 10-20 mm at its widest point, e.g.,about 13-16 mm or about 14.4 mm. The largest diameter of first flaredend region 102 may be selected so as to avoid mechanically loading thelimbus of the fossa ovalis 212, which might otherwise causeinflammation. The largest diameter of second flared end region 106 maybe selected so as to provide a sufficient angle between first and secondflared end regions 102, 106 to stabilize device 100 in the atrialseptum, while limiting the extent to which second flared end region 106protrudes into the left atrium (e.g., inhibiting interference with flowfrom the pulmonary veins), and providing sufficient blood flow from theleft atrium through neck region 104. In one embodiment, the anglebetween the first and second flared end regions is about 70-140 degrees,e.g., about 90 to 130 degrees, e.g., about 100 degrees. Such an anglemay stabilize device 100 across the fossa ovalis, while inhibitingexcessive contact between the device and the atrial septum. Suchexcessive contact might cause inflammation because of the expansion andcontraction of the atrial septum during the cardiac cycle, particularlybetween diastole and systole. In one embodiment, the first flared endregion subtends an angle of approximately 80 degrees, that is, thesteepest part of the outer surface of the first flared end region is atan angle of approximately 40 degrees relative to a central longitudinalaxis of the device. The second flared end region may flare by about30-70 degrees, where the steepest part of the outer surface of thesecond flared end region may be at an angle of approximately 35 degreesrelative to the central longitudinal axis of the device. The secondflare may be have a tapered shape starting with a wider angle in therange of about 50-70 degrees and end with a narrow angle in the range ofabout 30-40 degrees.

Tissue valve 130 is preferably configured such that when closed,leaflets 131 define approximately straight lines resulting from tensionexerted by stent 110 across valve opening 132, as illustrated in FIG.1C. Additionally, the transition between tissue valve 130 andbiocompatible material 120 preferably is smooth, so as to reduceturbulence and the possibility of flow stagnation, which would increasecoagulation and the possibility of blockage and excessive tissueingrowth. As pressure differentials develop across tissue valve 130(e.g., between the left and right atria), blood flow preferably followsa vector that is substantially perpendicular to the tension forcesexerted by stent 110, and as such, the equilibrium of forces isdisrupted and leaflets 131 start to open. As the leaflets open, thedirection of tension forces exerted by stent 110 change, enabling anequilibrium of forces and support of continuous flow. An equilibriumposition for each pressure differential is controlled by the geometry oftissue valve 130 and the elastic behavior of stent 110. When a negativepressure differential (right atrial pressure greater than left atrialpressure) develops, valve leaflets 131 are coapt, closing the tissuevalve and the prevention of right to left backflow.

When device 100 is implanted across the atrial septum, as illustrated inFIG. 2B, left atrial pressures may be regulated in patients havingcongestive heart failure (CHF). For example, device 100 may reducepressure in the left atrium by about 2-5 mmHg immediately followingimplantation. Such a pressure reduction may lead to a long-term benefitin the patient, because a process then begins by which the lowered leftatrial pressure reduces the transpulmonary gradient, which reduces thepulmonary artery pressure. However, the right atrial pressure is notsignificantly increased because the right atrium has a relatively highcompliance. Furthermore, the pulmonary capillaries may self-regulate toaccept high blood volume if needed, without increasing pressure. Whenthe left atrial pressure is high, the pulmonary capillaries constrict tomaintain the transpulmonary gradient, but as the left atrial pressuredecreases, and there is more blood coming from the right atrium, thereare actually higher flow rates at lower pressures passing through thepulmonary circulation. After a period of between a few hours and a weekfollowing implantation of device 100, the pulmonary circulation has beenobserved to function at lower pressures, while the systemic circulationmaintains higher pressures and thus adequate perfusion. The resultinglower pulmonary pressures, and lower left ventricle end diastolicpressure (LVEDP) decrease the after load by working at lower pressures,resulting in less oxygen demand and less resistance to flow. Such smalldecreases in afterload may dramatically increase the cardiac output (CO)in heart failure, resulting in increased ejection fraction (EF).Moreover, because of the release in the afterload and in the pressuresof the pulmonary circulation, the right atrial pressure decreases overtime as well. Following myocardial infarction, the effect is even morepronounced, because the period after the infarction is very importantfor the remodeling of the heart. Specifically, when the heart remodelsat lower pressures, the outcome is better.

In the region of contact between device 100 and atrial septum 210,preferably there is limited tissue growth. The connective tissue ofatrial septum 210 is non-living material, so substantially no nourishingof cells occurs between the septum and device 100. However, localstagnation in flow may lead to limited cell accumulation and tissuegrowth where device 100 contacts atrial septum 210, for example inregions designated 230 in FIG. 2B. Such tissue growth in regions 230 mayanchor device 210 across atrial septum 210. Additional, such tissuegrowth may cause the flow between the external surface of device 100 andatrial septum 210 to become smoother and more continuous, thus reducingor inhibiting further cell accumulation and tissue growth in regions230. As noted above, first flared end region 102 of stent 110, e.g.,between the line along which tissue valve 130 is coupled tobiocompatible material 120 and first sinusoidal ring 112 preferably isbare metal. This configuration is expected to inhibit formation ofstagnation points in blood flow in right atrium 204, that otherwise maylead to tissue growth on the external surfaces of leaflets 131 of tissuevalve 130.

A method 300 of making device 100 illustrated in FIGS. 1A-1D and FIG. 2Bwill now be described with respect to FIGS. 3A-3E.

First, a tube of shape-memory material, e.g., a shape-memory metal suchas nickel titanium (NiTi), also known as NITINOL, is provided (step 301of FIG. 3A). Other suitable materials known in the art of deformablestents for percutaneous implantation may alternatively be used, e.g.,other shape memory alloys, polymers, and the like. In one embodiment,the tube has a thickness of 0.25 mm.

Then, the tube is laser-cut to define a plurality of sinusoidal ringsconnected by longitudinally extending struts (step 302). For example,struts 111 and sinusoidal rings 112-116 illustrated in FIG. 1A may bedefined using laser cutting a single tube of shape-memory metal, andthus may form an integral piece of unitary construction. Alternatively,struts 111 and sinusoidal rings 112-116 may be separately defined fromdifferent pieces of shape-memory metal and subsequently coupledtogether.

Referring again to FIG. 3A, the laser-cut tube then is expanded on amandrel to define first and second flared end regions and a necktherebetween, e.g., to define first end region 102, second end region106, and neck region 104 as illustrated in FIG. 1A; the expanded tubethen may be heated to set the shape of stent 110 (step 303). In oneexample, the tube is formed of NITINOL, shaped using a shape mandrel,and placed into an oven for 11 minutes at 530 C to set the shape.Optionally, the stent thus defined also may be electropolished to reducethrombogenicity, or otherwise suitably treated. Such electropolishingmay alternatively be performed at a different time, e.g., before shapingusing the mandrel.

As shown in FIG. 3A, the neck and second flared end region of the stentthen may be coated with a biocompatible material (step 304). Examples ofsuitable biocompatible materials include expandedpolytetrafluoroethylene (ePTFE), polyurethane, DACRON (polyethyleneterephthalate), silicone, polycarbonate urethane, and animal pericardialtissue, e.g., from an equine, bovine, or porcine source. In oneembodiment, the stent is coated with the biocompatible material bycovering the inner surface of the stent with a first sheet of ePTFE, andcovering the outer surface of the stent with a second sheet of ePTFE.The first and second sheets first may be temporarily secured together tofacilitate the general arrangement, e.g., using an adhesive, suture, orweld, and then may be securely bonded together using sintering to form astrong, smooth, substantially continuous coating that covers the innerand outer surfaces of the stent. Portions of the coating then may beremoved as desired from selected portions of the stent, for exampleusing laser-cutting or mechanical cutting. For example, as shown in FIG.1A, biocompatible material 120 may cover stent 110 between sinusoidalring 113 and sinusoidal ring 116, i.e., may cover neck region 104 andsecond flared end region 106, but may be removed between sinusoidal ring113 and sinusoidal ring 112, i.e., may be removed from (or not appliedto) first flared end region 102.

The biocompatible material facilitates funneling of blood from the leftatrium to the right atrium by facilitating the formation of a pressuregradient across tissue valve 130, as well as providing a substantiallysmooth hemodynamic profile on both the inner and outer surfaces ofdevice 100. Advantageously, this configuration is expected to inhibitthe formation of eddy currents that otherwise may cause emboli to form,and facilitates smooth attachment of the device to the atrial septum,e.g., fossa ovalis. Biocompatible material 120 preferably is configuredso as to direct blood flow from the left atrium, through neck region 104and toward tissue valve leaflets 131. Biocompatible material 120preferably also is configured so as to inhibit tissue growth from atrialseptum 210 and surrounding tissue into device 100 and particularlytoward tissue valve leaflets 131. In some embodiments, the biocompatiblematerial 120 has a porosity that is preselected to allow limited cellgrowth on its surface; the cells that grow on such a surface preferablyare endothelial cells that are exposed to blood and inhibit blood fromcoagulating on the biocompatible material. After such cells grow on thebiocompatible material 120, the material preferably is substantiallyinert and thus not rejected by the body. Optionally, the biocompatiblematerial may be impregnated with a second material that facilitatestissue ingrowth, e.g., carbon. Such impregnation may be performed beforeor after applying the biocompatible material to the stent.

Then, as shown in FIG. 3A, a valve having two or more leaflets, such asa tricuspid, bicuspid, or duckbill valve, or any other suitable valve,is formed by folding and suturing a sheet of thinned animal pericardialtissue, e.g., equine, bovine, or porcine material (step 305). FIGS.3B-3E illustrate plan views of exemplary sheets of animal pericardialtissue that may be used to form tissue valves. Specifically, FIG. 3Billustrates an approximately semicircular sheet 310 of tissue for use inpreparing a tricuspid tissue valve. Although the sheet 310 may be anysuitable dimensions, in the illustrated embodiment the sheet has a widthof 10-16 mm, a length of 6-8 mm. The opposing edges may be at an anglebetween 0-70 degrees relative to one another so that when the sheet isfolded and those edges are secured, e.g., sutured together, sheet 310forms a generally funnel-like shape having approximately the same angleas the first flared end region to which it is to be secured. FIG. 3Cillustrates an embodiment similar to that of FIG. 3B, but in which sheet320 also includes wings 321 providing additional tissue material inregions along the suture line that may be subjected to high stresses, aswell as a curved top contour 322 that provides an extended region forcoaptation between the leaflets when the valve is closed. Wings may beapproximately 2-5 mm long, and extend 0.5-1.5 mm beyond the lateraledges of sheet 320. FIG. 3D illustrates an embodiment similar to that ofFIG. 3C, e.g., that includes wings 331 that may be of similar dimensionas wings 321, but in which sheet 330 lacks a curved top contour. Sutures332 are shown in FIG. 3D. FIG. 3E illustrates a sheet 340 of tissuesuitable for use in preparing a bicuspid tissue valve, that has agenerally rectangular shape, for example having a width of 14-15 mm anda length of 6.0-7.0 mm. Other dimensions may suitably be used. Forexample, the tissue sheet may have a flattened length of no greater than18 mm, for example, a length of 10-16 mm, or 12-14 mm, or 14-18 mm, andmay be folded and sutured to define two or more leaflets each having alength of, for example, 9 mm or less, or 8 mm or less, or 7 mm or less,or 6 mm or less, or even 5 mm or less, e.g., 5-8 mm. The tissue sheetmay have a flattened height no greater than 10 mm, for example, a heightof 2-10 mm, or 4-10 mm, or 4-8 mm, or 6-8 mm, or 4-6 mm. The tissuesheet may have a flattened area of no greater than 150 square mm, forexample, 60-150 square mm, or 80-120 square mm, or 100-140 square mm, or60-100 square mm. In some exemplary embodiments, the sheet of tissue mayhave a generally trapezoidal or “fan” shape, so that when opposing edgesare brought together and sutured together, the sheet has a general“funnel” shape, with a wide opening along the outlet or upper edge and anarrow opening along the inlet or lower edge. Note that other suitablemethods of securing opposing edges of the sheet alternatively may beused, e.g., adhesive, welding, and the like.

The tissue may have a thickness, for example, of between 0.050 mm and0.50 mm, for example, about 0.10 mm and 0.20 mm. Typically, harvestedbovine pericardial tissue has a thickness between about 0.3 mm and 0.5mm, which as is known in the art is a suitable thickness for high-stressapplications such as construction of aortic valves. However, for use inthe device of the present invention, it may be preferable to thin thepericardial tissue. For example, the stresses to which the valveleaflets are exposed in a device constructed in accordance with thepresent invention may be a small fraction (e.g., 1/25th) of the stressesin an aortic valve application, because of the relatively large surfacearea of the leaflets and the relatively low pressure gradients acrossthe device. For this reason, thinned pericardial tissue may be used,enabling construction of a more compliant valve that may be readilyfixed in a normally closed position but that opens under relatively lowpressure gradients. Additionally, the use of thinner leaflets isexpected to permit the overall profile of the device to be reduced inwhen the device is compressed to the contracted delivery state, therebyenabling its use in a wider range of patients.

For example, harvested pericardial tissue typically includes threelayers: the smooth and thin mesothelial layer, the inner looseconnective tissue, and the outer dense fibrous tissue. The pericardialtissue may be thinned by delaminating and removing the dense fibroustissue, and using a sheet of the remaining mesothelial and looseconnective layers, which may have a thickness of 0.10 mm to 0.20 mm, toconstruct the tissue valve. The dense fibrous tissue may be mechanicallyremoved, for example using a dermatome, grabbing tool, or by hand, andany remaining fibers trimmed.

The animal pericardial tissue then may be three-dimensionally shaped ona mandrel to define a tissue valve having valve leaflets that arenormally in a closed position, and then fixed in that position usingglutaraldehyde or other suitable substance (step 306). Excessglutaraldehyde may be removed using an anticalcification treatment, forexample to inhibit the formation of calcium deposits on the tissuevalve.

The outlet or upper (wider) portion of the tissue valve then may besecured, e.g., sutured, to the first flared end region, and the inlet orlower (narrower) portion of the tissue valve secured, e.g., sutured tothe biocompatible polymer at the neck region (step 307). For example, asillustrated in FIGS. 1A-1D, the lower portion of tissue valve 130 may besecured using sutures to biocompatible material 120 at or nearsinusoidal ring 113 (for example, along a line 121 approximately 2-3 mmto the right of the narrowest portion of neck region 104), and also maybe sutured to elongated struts 111′, 111″, and 111′″ so as to define atricuspid valve having leaflets 131. Other suitable methods of securingthe tissue valve to stent 110 and to biocompatible material 120 mayalternatively be used. Preferably, tissue valve 130 is secured to device100 such that, when implanted, the tissue valve is disposedsubstantially only in the right atrium. Such a configuration mayfacilitate flushing of the external surfaces of leaflets 131 with bloodentering the right atrium. By comparison, it is believed that ifleaflets 131 were instead disposed within neck region 104 or secondflared end region 106, they might inhibit blood flow and/or graduallylose patency over time as a result of tissue ingrowth caused by thestagnation of blood around the leaflets.

A method 400 of using device 100 illustrated in FIGS. 1A-1D to reduceleft atrial pressure in a subject, for example, a human having CHF, willnow be described with reference to FIG. 4. Some of the steps of method400 may be further elaborated by referring to FIGS. 5A-5D.

First, an hourglass-shaped device having a plurality of sinusoidal ringsconnected by longitudinally extending struts that define first andsecond flared end regions and a neck disposed therebetween, as well as atissue valve coupled to the first flared end region, is provided (step401). Such a device may be provided, for example, using method 300described above with respect to FIGS. 3A-3E.

Then, the device is collapsed radially to a contracted delivery state,and loaded into a loading tube (step 402). For example, as illustratedin FIGS. 5A-5B, device 100 may be loaded into loading tube 510 usingpusher 520 having “star”-shaped end 521. Loading tube 510 includestapered loading end 511, which facilitates radial compression of device100 into lumen 512 having a suitable internal diameter. Once device 100is loaded into lumen 512, pusher 520 is retracted. Preferably, device100 is loaded into loading tube 510 shortly before implantation, so asto avoid unnecessarily compressing device 100 or re-setting of theclosed shape of leaflets 132, which may interfere with later deploymentor operation of the device. In some embodiments, loading tube 510 has adiameter of 16 F or less, or 14 F or less, or 10 F or less, or 6 F orless, e.g., about 5 F, and device 100 has a crimped diameter of 16 F orless, or 14 F or less, or 10 F or less, or 6 F or less, e.g., about 5 F.In one illustrative embodiment, loading tube has a diameter of 15 F anddevice 100 has a crimped diameter of 14 F.

Referring again to FIG. 4, the device then is implanted, first byidentifying the fossa ovalis of the heart septum, across which device100 is to be deployed (step 403). Specifically, a BROCKENBROUGH needlemay be percutaneously introduced into the right atrium via the subject'svenous vasculature, for example, via the femoral artery. Then, underfluoroscopic or echocardiographic visualization, the needle is pressedagainst the fossa ovalis, at a pressure insufficient to puncture thefossa ovalis. As illustrated in FIG. 5C, the pressure from needle 530causes “tenting” of fossa ovalis 541, i.e., causes the fossa ovalis tostretch into the left atrium. Other portions of atrial septum 540 arethick and muscular, and so do not stretch to the same extent as thefossa ovalis. Thus, by visualizing the extent to which differentportions of the atrial septum 540 tents under pressure from needle 530,fossa ovalis 541 may be identified, and in particular the centralportion of fossa ovalis 541 may be located.

Referring again to FIG. 4, the fossa ovalis (particularly its centralregion) may be punctured with the BROCKENBROUGH needle, and a guidewiremay be inserted through the puncture by threading the guidewire throughthe needle and then removing the needle (step 404, not illustrated inFIG. 5). The puncture through the fossa ovalis then may be expanded byadvancing a dilator over the guidewire. Alternatively, a dilator may beadvanced over the BROCKENBROUGH needle, without the need for aguidewire. The dilator is used to further dilate the puncture and asheath then is advanced over the dilator and through the fossa ovalis;the dilator and guidewire or needle then are removed (step 405, notillustrated in FIG. 5). The loading tube, with device 100 disposed in acontracted delivery state therein, then is advanced into the sheath(step 406, not illustrated in FIG. 5).

The device then is advanced out of the loading tube and into the sheathusing a pusher, and then partially advanced out of the sheath, such thatthe second flared end of the device protrudes out of the sheath and intothe left atrium, and expands to its deployed state (step 407). Forexample, as illustrated in FIG. 5D, pusher 550 may be used to partiallyadvance device 100 out of sheath 512 and into left atrium 502, whichcauses the second flared end region to expand in the left atrium. Thepusher may be configured such that it cannot advance the device 100completely out of the sheath, but instead may only push out the side ofthe device to be disposed in the left atrium, that is, the second flaredend region. After the pusher advances the second flared end region outof the sheath, the pusher may be mechanically locked from advancing thedevice out any further. For example, an expanded region may be disposedon the end of the pusher proximal to the physician that abuts the sheathand prevents further advancement of the pusher after the second flaredend region is advanced out of the sheath. The device then may be fullydeployed by pulling the sheath back, causing the second flared endregion of the device to engage the left side of the atrial septum. Sucha feature may prevent accidentally deploying the entire device in theleft atrium.

The sheath then is retracted, causing the second flared end region toflank the left side of the atrial septum and the neck of the device tolodge in the puncture through the fossa ovalis, and allowing expansionof the first flared end of the device into the right atrium (step 408,see also FIG. 2B). Any remaining components of the delivery system thenmay be removed, e.g., sheath, and loading tube (step 409). Oncepositioned in the fossa ovalis, the device shunts blood from the leftatrium to the right atrium when the left atrial pressure exceeds theright atrial pressure (step 410), thus facilitating treatment and/or theamelioration of symptoms associated with CHF.

The performance characteristics of device 100 were characterized usingcomputational fluid dynamic modeling. FIG. 6A is a cross-sectional imageof fluid flow through device 100 in the open configuration, in whichintensity indicates fluid velocity through the device. As can be seen inFIG. 6A, there are substantially no points of stagnation or turbulencein the blood flow. The maximum shear stresses within device 100 werecalculated to be about 50-60 Pascal, which is significantly lower thanvalues that may lead to thrombus formation, which are above 150 Pascal.

The performance of device 100 was also characterized using hemodynamictesting. FIG. 6B is a plot of the flow rate through device 100 as afunction of the pressure differential between the left and right atria,for devices having inner diameters of 3.5 mm (trace 610), 4.2 mm (trace620), 4.8 mm (trace 630), and 5.2 mm (trace 640). At a pressuredifferential of 10 mm Hg, it can be seen that the flow rate of the 3.5mm device was 670 ml/minute; the flow rate of the 4.2 mm device was 1055ml/minute; the flow rate of the 4.8 mm device was 1400 ml/minute; andthe flow rate of the 5.2 mm device was 1860 ml/minute. Based on thesemeasurements, it is believed that devices having inner diameters of 4.5mm to 4.8 mm may provide suitable flow parameters over time, whenimplanted, because ingrowth of septal tissue over the first 6 monthsfollowing implantation may reduce the inner diameter to about 3.5 to 3.8mm, thus reducing the flow rate to below about 800 ml/minute. At steadystate, such a flow rate may reduce the left atrial pressure by 5 mmHg,to around 10-15 mmHg, and may reduce the pressure differential betweenthe left and right atria to about 4-6 mmHg.

Additionally, device 100 was subjected to an accelerated wear andfatigue test for up to 100 million cycles to simulate and predictfatigue durability, and was observed to perform satisfactorily.

The devices and methods described herein may be used to regulate leftatrial pressures in patients having a variety of disorders, includingcongestive heart failure (CHF), as well as other disorders such aspatent foramen ovale (PFO), or atrial septal defect (ASD). The devicesand methods also may be used to reduce symptoms and complicationsassociated with such disorders, including myocardial infarction. It isbelieved that patients receiving the device may benefit from betterexercise tolerance, less incidence of hospitalization due to acuteepisodes of heart failure, and reduced mortality rates.

The devices and methods described herein further may be used tonon-invasively determine the pressure in the left atrium, and thus toassess the efficacy of the device and/or of any medications beingadministered to the patient. Specifically, with respect to FIG. 7,method 700 includes imaging an implanted hourglass-shaped device, e.g.,device 100 described above with respect to FIGS. 1A-1D (step 701). Suchimaging may be ultrasonic, e.g., cardioechographic, or may befluoroscopic. Using such imaging, the time duration of the opening oftissue valve 130 may be measured (step 702). Based on the measured timeduration, the flow of blood through the valve may be calculated (step703). The left atrial pressure then may be calculated based on thecalculated flow, for example, based on a curve such as shown in FIG. 6B(step 704). Based on the calculated left atrial pressure, the efficacyof the valve and/or of any medication may be assessed (step 705). Aphysician may adjust the medication and/or may prescribe a new treatmentplan based on the assessed efficacy of the valve and/or the medication.

Some alternative embodiments of device 100 described above with respectto FIGS. 1A-1D are now described. In particular, tissue valves otherthan tricuspid valve 130 illustrated above with respect to FIGS. 1A-1Dmay be employed with device 100. For example, device 800 illustrated inFIGS. 8A-8C includes hourglass-shaped stent 110, which may besubstantially the same as stent 110 described above, biocompatiblematerial 120, and duckbill tissue valve 830. Like device 100, device 800has three general regions: first flared or funnel-shaped end region 102configured to flank the right side of the atrial septum, second flaredor funnel-shaped end region 106 configured to flank the left side of theatrial septum, and neck region 104 disposed between the first and secondflared end regions and configured to lodge in a puncture formed in theatrial septum, preferably in the fossa ovalis. Stent 110 includesplurality of sinusoidal rings 112-116 interconnected by longitudinallyextending struts 111, which may be laser cut from a tube of shape memorymetal. Neck region 104 and second flared end region 106 may be coveredwith biocompatible material 120, e.g., in the region extendingapproximately from sinusoidal ring 113 to sinusoidal ring 116.

Duckbill tissue valve 830 is coupled to stent 110 in first flared endregion 102. Preferably, tissue valve 830 opens at a pressure of lessthan 1 mmHg, closes at a pressure gradient of 0 mmHg, and remains closedat relatively high back pressures, for example at back pressures of atleast 40 mmHg. Like tissue valve 130, tissue valve 830 may be formedusing any natural or synthetic biocompatible material, including but notlimited to pericardial tissue, e.g., thinned and fixed bovine, equine,or porcine pericardial tissue. As shown in FIG. 8B, the outlet ofduckbill tissue valve 830 is coupled, e.g., sutured, to first and secondlongitudinally extending struts 111′, 111″ in the region extendingbetween first (uppermost) sinusoidal ring 112 and second sinusoidal ring113. Referring again to FIG. 8A, the inlet to tissue valve 830 also iscoupled, e.g., sutured, to the upper edge of the biocompatible material120 along line 121, at or near sinusoidal ring 113, so as to provide asmooth profile.

FIGS. 8A and 8B illustrate device 800 when duckbill tissue valve 830 isin an open configuration, in which leaflets 931 are in an open positionto permit flow. FIG. 8C illustrates device 800 when tissue valve 830 isin a closed configuration, in which leaflets 831 are in a closedposition to inhibit flow, in which position they preferably form asubstantially straight line. Device 800 preferably is configured so asto provide flow characteristics similar to those described above fordevice 100.

Referring now to FIG. 9, alternative device of the present invention isdescribed. Device 900 has first and second flared end regions 902, 906,with neck region 904 disposed therebetween. Device 900 includeshourglass-shaped stent 910, biocompatible material 920, and tissue valve930 and further comprises three general regions as described for theforegoing embodiments: first flared or funnel-shaped end region 902configured to flank the right side of the atrial septum, second flaredor funnel-shaped end region 906 configured to flank the left side of theatrial septum, and neck region 904 disposed between the first and secondflared end regions and configured to lodge in a puncture formed in theatrial septum, preferably in the fossa ovalis. Like the devicesdescribed above, stent 910 includes plurality of sinusoidal rings 912interconnected by longitudinally extending struts 911, which may belaser cut from a tube of shape memory metal. However, as compared todevices 100 and 800 described further above, sinusoidal rings 912 do notextend into first flared end region 902. Instead, the outlet end oftissue valve 930 is coupled to longitudinally extending struts 911′ and911″. Neck region 904 and second flared end region 906 may be coveredwith biocompatible material 920.

Duckbill tissue valve 930 is coupled to stent 910 in first flared endregion 902. Specifically, the outlet of tissue valve 930 is coupled,e.g., sutured, to first and second longitudinally extending struts 911′,911″ in the region extending between the first (uppermost) sinusoidalring 912 and the distal ends of struts 911′, 911″. The inlet end oftissue valve 930 also is coupled, e.g., sutured, to the upper edge ofbiocompatible material 920 at or near first (uppermost) sinusoidal ring912, so as to provide a smooth profile. Device 900 is preferablyconfigured so as to provide flow characteristics similar to thosedescribed above for device 100.

EXAMPLE

An exemplary device 800 such as described above with respect to FIGS.8A-8C was implanted into four sheep with induced chronic heart failure(V1-V4), while four sheep with induced chronic heart failure did notreceive the device, and were used as a control (C1-C4). An additionalcontrol animal was subjected to only a partial heart failure protocol,and did not receive the device (S1).

Chronic heart failure was induced in animals C1-C4 and V1-V4, who wereless than 1 year of age and weighed between 70 and 120 pounds, by firstanesthetizing the animals via a venous catheter positioned in aperipheral vessel, i.e., the ear. The animals were given an opiate orsynthetic opiate (e.g., morphine or butorphanol) intravenously at 0.25to 0.5 mg/kg, as well as telazol at 0.3 mg/kg, through the venouscatheter, and anesthetized by intravenous etomidate. Anesthesia wasmaintained with 1.5% isoflurane delivered in 100% O₂, via a trachealtube. The animals were placed on a fluoroscope table in left lateralrecumbence, and a gastric tube (about 7 F) was inserted into the rumento serve as a vent.

An introducer was then positioned within the carotid artery via cut downand modified Seldinger technique. A 6 F or 7 F Judkins left 4.5 catheterwas advanced through the introducer into the left circumflex coronaryartery (LCxA) under fluoroscopic guidance, and about 60,000 polystyrenemicrospheres of about 90 μm diameter were injected into the LCxA toinduce embolization to induce myocardial infarction followed by chronicheart failure. The arterial and skin incisions then were closed, and theanimals were administered about 500 mg of cephalexein p.o. bid for twodays, as well as a synthetic opiate pm, specifically buprenorphineadministered intramuscularly at about 0.03 to 0.05 mg/kg, once duringrecovery and following the anesthesia. Animals observed to havearrhythmia following or during the microsphere injection were alsoadministered lidocaine following embolization, at about 2 to 4 mg/kg viaintravenous bolus, followed by constant infusion at about 20 to 80μf/kf/minute.

This procedure was repeated one week following the first procedure inanimals V1-V4 and C1-C4. This model of induced chronic heart failure hasabout a 100% fatality rate at 12 weeks, and as discussed below each ofthe control animals died before the end of the 12 week study. Theprocedure was performed a single time in animal S1, and as discussedbelow this animal survived the 12 week study but deteriorated over thecourse of the study.

Device 800 was implanted into four animals V1-V4. Fluid filled catheterswere implanted into animals V1-V4 and C1-C4, approximately seven daysafter the second embolization procedure. Fluid filled catheters were notimplanted into animal S1. The implanted device 800 had an overall lengthof 15 mm (7 mm on the left atrial side and 8 mm on the right atrialside), a diameter on the left atrial side of 14 mm, a diameter on theright atrial side of 13 mm, an inside neck diameter of 5.3 mm, and anangle between the left and right atrial sides of the device of 70degrees. The fluid filled catheters were implanted in the inferior venacava (IVC), superior vena cava (SVC), pulmonary artery, and left atriumthrough a right mini-thoracotomy under anesthesia, and were configuredto measure oxygen saturations and pressures in the IVC, pulmonaryartery, right atrium, and left atrium. After implantation and throughoutthe study, the animals were each treated daily with aspirin, plavix, andclopidogrel. Their heart rate was periodically monitored.

Two-dimensional M-mode echocardiograms of the left ventricle wereperiodically obtained to document the ejection fraction (EF), as well asthe shortening fraction, calculated as 100(EDD−ESD)/EDD, where EDD isthe end-diastolic dimension (diameter across ventricle at the end ofdiastole) and ESD is the end-systolic dimension (diameter acrossventricle at the end of systole). Echocardiographic studies of theanimals were performed while they were either conscious or under lightchemical restraint with butorphanol, and manually restrained in theright or left decubitis position, using an ultrasound system with a 3.5to 5.0 mHz transducer (Megas ES, model 7038 echocardiography unit). Theechocardiograms were recorded for subsequent analysis. The leftventricle fractional area shortening (FAS), a measure of left ventriclesystolic function, was measured from the short axis view at the level ofthe papillary muscles. Measurements of left ventricle dimensions,thickness of the posterior wall, and intraventricular septum wereobtained and used as an index of left ventricle remodeling. The majorand minor axes of the left ventricle were measured and used to estimateleft ventricle end-diastolic circumferential wall stress.

The clinical conditions of the animals were evaluated by comparingvarious parameters over a twelve-week period, including left atrialpressure, right atrial pressure, pulmonary artery pressure, and ejectionfraction (EF). Parameters such as left and right atrial pressures, leftand right ventricular dimensions, and left and right ventricularfunction were obtained based on the collected data. Data obtained duringthe study are discussed further below with respect to FIGS. 10A-10D andTables 2-15.

During the course of the study, all four of the control animals C1-C4were observed to suffer from high pulmonary artery pressure, high rightatrial pressure, and low ejection fraction, and were immobile. All fourcontrol animals died during the trial, C3 at week 1, C4 at week 3, C1 atweek 6, and C2 at week 9. Animal S1 survived but deteriorated over thecourse of the study.

By comparison, all of the animals V1-V4 into which the device had beenimplanted were observed to have dramatically improved hemodynamicconditions over the course of the study, and appeared healthy andenergetic without signs of congestion by the end of the study. Asdiscussed below with reference to FIGS. 10A-10D, device 800 was observedto reduce left atrial pressure in the implanted animals by about 5 mmHg,with an increase in cardiac output, and preservation of right atrialpressure and pulmonary artery pressure. Left ventricle parameters wereobserved to be substantially improved in the implanted animals ascompared to the control animals, and right ventricle and pulmonaryartery pressure were also observed to be normal in the implantedanimals.

Three of the four implanted animals, V1, V3, and V4 survived the twelveweek study. One of the implanted animals, V2, died at week 10 of anon-heart failure cause. Specifically, arrhythmia was diagnosed as thecause of death; the animal was observed to have arrhythmia at baseline,and had been defibrillated before implantation Throughout the study,this animal was observed to have good hemodynamic data. At the end ofthe study, the surviving implant animals were observed to respondnormally to doses of dobutamine, indicating significant improvement inthe condition of their heart failure.

FIG. 10A is a plot of the measured left atrial pressure of the controlanimals (C1-C4), and of the implanted animals (V1-V4), along with meanvalues for each (M.C. and M.V., respectively). Data for control animalC3 is not shown, as the animal died in the first week of the study. Themean left atrial pressure for the control animals (M.C.) was observed tosteadily increase over the course of the study, from about 14 mmHg atbaseline to over 27 mmHg when the last control animal (C1) died. Bycomparison, the mean left atrial pressure for the implanted animals(M.V.) was observed to drop from about 15 mmHg at baseline to less than12 mmHg at week one, and to remain below 14 mmHg throughout the study.

FIG. 10B is a plot of the measured right atrial pressure of the controlanimals (C1-C4), and of the implanted animals (V1-V4), along with meanvalues for each (M.C. and M.V., respectively). Data for control animalC3 is not shown. As for the left atrial pressure, the mean right atrialpressure for the control animals (M.C.) was observed to steadilyincrease over the course of the study, from about 5.5 mmHg at baselineto over 12 mmHg when the last control animal (C1) died. By comparison,the mean right atrial pressure for the implanted animals (M.V.) wasobserved to remain relatively steady throughout the study, increasingfrom about 6 mmHg to about 7 mm Hg over the first two weeks of thestudy, and then decreasing again to about 6 mmHg for the rest of thestudy.

FIG. 10C is a plot of the measured ejection fraction of the controlanimals (C1-C4), and of the implanted animals (V1-V4), along with meanvalues for each (M.C. and M.V., respectively). Data for control animalC3 is not shown. The mean ejection fraction for the control animals(M.C.) was observed to steadily decrease over the course of the study,from about 38% at baseline to about 16% when the last control animal(C1) died. By comparison, the mean ejection fraction for the implantedanimals (M.V.) was observed to steadily increase over the course of thestudy, from about 33% at baseline to about 46% at the conclusion of thestudy.

FIG. 10D is a plot of the measured pulmonary artery pressure of thecontrol animals (C1-C4), and of the implanted animals (V1-V4), alongwith mean values for each (M.C. and M.V., respectively). Data forcontrol animal C3 is not shown. The mean pulmonary artery pressure forthe control animals (M.C.) was observed to vary significantly over thecourse of the study, from about 27 mmHg during the first week of thestudy, to about 45 mmHg at week six, then down to 40 mmHg at week eight,and then up to about 47 mmHg at week nine, when the last control animal(C1) died. By comparison, the mean pulmonary artery pressure for theimplanted animals (M.V.) was observed to remain relatively steady,increasing from about 22 mmHg during week one, to about 27 mmHg duringweeks four through nine, and then back down to about 24 mmHg by weektwelve, at the conclusion of the study.

Upon explantation at the end of the study, three of the four implanteddevices were observed to be completely patent and functional. Forexample, FIGS. 11A-11B are photographic images of device 800 uponexplantation from one of the implanted animals, taken from the leftatrial and right atrial sides respectively. A fourth device was observedto be patent up until week 11, using Fick's measurements andechocardiography. At histopathology, no inflammation was observed aroundthe valves, and a thin endothelial layer was observed to have ingrown.For example, FIG. 11C is a microscope image of device 800 uponexplantation from one of the implanted animals, showing approximately0.2 mm of endothelial tissue in the device in the neck region.

Tables 2 through 15 present raw data obtained from the control animalsC1-C4 and S1 and the implanted animals V1-V4, while awake, over thecourse of the 12 week study, including baseline immediately beforeimplantation (Day 0, during which the animals were sedated). The meanvalues for control animals C1-C4 and S1 (M.C.) and the mean values forthe implanted animals V1-V4 (M.V.), with standard deviations, are alsopresented in the tables. Missing data indicates either the death of theanimal or omission to obtain data. Data for animal C3 is not shownbecause the animal died in the first week of the study. Data was notcollected for any animal in week 7 of the study. As noted above, animalS1 was not implanted with pressure and saturation flow monitors, so nodata is shown for that animal for certain measurements.

Table 2 presents the study's results pertaining to right atrial pressure(RAP, mmHg). As can be seen from Table 2, the average RAP for thecontrol animals (C1-C4) increased significantly over the course of thestudy. For example, animal C1 experienced an RAP increase to about 330%of baseline before death, C2 to about 110% of baseline before death, andC4 to about 340% of baseline before death. The increase was relativelysteady during this period. By contrast, the RAP for the implantedanimals (V1-V4) started at a similar value to that of the controlanimals, at an average of 6±2 mmHg at baseline, but did notsignificantly vary over the course of the study. Instead, the averageRAP of the implanted animals remained within about 1-2 mmHg of thebaseline value for the entire study (between a high of 7±1 and a low of5±1). Thus, the inventive device may inhibit increases in the rightatrial pressure in subjects suffering from heart failure, and indeed maymaintain the right atrial pressure at or near a baseline value. This isparticularly noteworthy because, as described elsewhere herein, thedevice may offload a relatively large volume of blood from the leftatrium to the right atrium; however the relatively high compliance ofthe right atrium inhibits such offloading from significantly increasingRAP.

TABLE 2 Right Atrial Pressure (RAP, mmHg) Day 0 Wk. 1 Wk. 2 Wk. 3 Wk. 4Wk. 5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C1 3.8 4.3 5.1 4.1 10.811.6 12.1 12.8 12.6 C2 9.2 10.1 10.5 9.8 8.6 9.8 10.3 C4 3.3 5.7 6.111.4 S1 V1 8.9 7.1 8.2 5.6 6.8 5.7 6.1 6.9 7.1 6.5 5.7 6.3 V2 7.4 6.16.7 5.5 5.6 6.0 6.4 7.0 6.5 V3 8.0 7.7 7.7 7.6 6.7 6.0 5.5 5.8 5.4 6.77.2 5.7 V4 0.9 5.2 5.1 4.9 5.7 5.8 3.4 3.8 4.8 5.0 5.6 5.7 M.C. 5 ± 2 7± 2 7 ± 1 8 ± 2 10 ± 1 11 ± 1 11 ± 1 13 13 M.V. 6 ± 2 7 ± 1 7 ± 1 6 ± 1 6 ± 0  6 ± 0  5 ± 1 6 ± 1 6 ± 1 6 ± 1 6 ± 1 6 ± 0

Table 3 presents the study's results pertaining to left atrial pressure(LAP, mmHg). As can be seen from Table 3, the average LAP of the controlanimals started at a similar value at baseline as that of the implantedanimals, 14±1 mmHg for the former and 15±2 mmHg for the latter. However,the LAP of the control animals increased significantly over the courseof the study. For example, animal C1 had a baseline LAP of 10.6 mmHg,and an LAP of 27.3 mmHg at week 9 just before death, about 250% ofbaseline. The LAP increases of the other control animals were smaller,but still significantly larger than that of the implanted animals.Indeed, in each case the LAP of the implanted animals actually decreasedimmediately following implantation. For example, the LAP for animal V1decreased from 15.7 mmHg at baseline to 11.4 mmHg one week followingimplantation, about 73% of baseline. The average LAP for the implantedanimals decreased from 15±2 at baseline to a low of 11±0 at week one,and then gradually increased to about 13±1 at week six (about 87% ofbaseline), where it remained for the remainder of the study.

TABLE 3 Left Atrial Pressure (LAP, mmHg) Day 0 Wk. 1 Wk. 2 Wk. 3 Wk. 4Wk. 5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C1 10.6 12.8 15.9 13.6 17.023.5 24.4 26.0 27.3 C2 14.4 15.1 16.3 18.1 18.1 19.7 20.7 C4 16.4 17.718.9 23.7 S1 V1 15.7 11.4 11.3 8.8 9.2 13.4 14.3 15.0 14.9 13.9 15.215.6 V2 19.8 11.7 11.7 12.1 12.3 13.0 14.7 14.2 14.0 V3 14.3 12.1 12.412.7 12.0 11.5 11.6 11.8 11.9 12.4 13.0 12.3 V4 10.3 10.1 11.3 11.4 11.010.2 10.8 11.2 11.7 11.9 12.2 12.1 M.C. 14 ± 1 15 ± 1 17 ± 1 18 ± 3 18 ±0 22 ± 2 23 ± 2 26 27 M.V. 15 ± 2 11 ± 0 12 ± 0 11 ± 1 11 ± 1 12 ± 1 13± 1 13 ± 1 13 ± 1 13 ± 1 13 ± 1 13 ± 1

Table 4 further elaborates the results presented in Table 3, andpresents the calculated change in LAP (ALAP, %). As can be seen in Table4, control animals C2 and C4 each died after their LAP increased byabout 44%, while control animal C1 died after its LAP increased by about158%. By comparison, implanted animals V1, V2, and V3 each experiencedsignificant decreases in LAP immediately following implantation, e.g.,by about −27%, −41%, and −15% relative to baseline. The LAP for animalV4 remained near baseline following implantation. The LAP for animal V1slowly increased back to baseline over the course of the study; the LAPfor animal V2 remained significantly below baseline before its death butincreased somewhat; the LAP for animal V3 also remained below baselinethroughout the study but increased somewhat; and the LAP for animal V4fluctuated somewhat above baseline but remained within about 18% ofbaseline. Thus, it can be seen that the inventive device may inhibitincreases in the left atrial pressure in patients suffering from heartfailure. Indeed, the device may actually decrease the left atrialpressure below baseline in patients suffering from heart failure for atime period immediately following implantation, in some embodiments to alevel about 20% below baseline. The left atrial pressure subsequentlymay gradually increase back towards a baseline level over a time periodof weeks or months, as the heart remodels and improves in efficiency. Itis important to note that the control animals died from pulmonary edema,which correlates with LAPs that exceed the “danger zone” of 25 mmHg ormore at which edema occurs.

TABLE 4 Change in Left Atrial Pressure (ΔLAP, %) Day 0 Wk. 1 Wk. 2 Wk. 3Wk. 4 Wk. 5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C1 +5 +51 +29 +61+122 +131 +145 +158 C2 +21 +14 +26 +26 +37 +44 C4 +8 +15 +44 S1 V1 −27−28 −44 −41 −15 −9 −4 −5 −11 −3 0 V2 −41 −41 −39 −38 −34 −26 −28 −29 V3−15 −13 −11 −16 −20 −19 −17 −16 −13 −9 −13 V4 −2 +10 +10 +7 −1 +5 +8 +13+16 +18 +17 M.C. +11 ± 4 +27 ± 10 +33 ± 5  +44 ± 14 +80 ± 42 +87 ± 35+145 +158 M.V. −21 ± 8 −18 ± 11 −21 ± 13 −22 ± 11 −17 ± 7  −12 ± 7  −10± 8 −9 ± 9 −3 ± 9 +2 ± 8 +1 ± 9

Table 5 presents the study's results pertaining to pulmonary arterypressure (PAP, mmHg). As can be seen in Table 5, the control animalsexperienced significant increases in PAP before death, e.g., about 230%of baseline for animal C1, 217% of baseline for animal C2, and 180% ofbaseline for animal C4. The PAP for the implanted animals also increasedover the course of the study, but in most cases by significantly lessthan that of the control animals, e.g., to about 133% of baseline foranimal V1, about 161% of baseline for animal V2, about 156% of baselinefor animal V3, and about 169% for animal V4. The inventive device thusmay inhibit increases in pulmonary artery pressure in subjects sufferingfrom heart failure, relative to what they may otherwise have experiencedduring heart failure.

TABLE 5 Pulmonary Artery Pressure (PAP, mmHg) Day 0 Wk. 1 Wk. 2 Wk. 3Wk. 4 Wk. 5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C1 20.8 27.9 28.527.9 28.0 41.7 40.2 48.0 C2 22.3 25.8 29.7 26.9 32.0 43.5 48.4 C4 20.128.4 31.2 36.1 S1 V1 18.6 21.2 20.7 27.1 30.2 28.4 29.0 29.8 29.2 27.126.3 24.8 V2 20.9 21.5 21.4 21.9 25.4 29.7 33.0 33.0 33.6 V3 14.1 22.023.3 23.5 23.1 22.6 21.0 21.6 21.8 22.6 22.0 22.0 V4 14.0 24.1 24.2 24.126.8 22.0 23.4 24.3 24.2 24.7 25.0 23.6 M.C. 21 ± 1 27 ± 1 30 ± 1 30 ± 330 ± 2 43 45 ± 3 40 48 M.V. 17 ± 2 22 ± 1 22 ± 1 24 ± 1 26 ± 1 26 ± 2 27± 3 27 ± 3 27 ± 3 25 ± 1 24 ± 1 23 ± 1

Table 6 presents the study's results pertaining to heart rates (HR,beats per minute). During each week of the study, except for week one,it can be seen that the heart rates of the control animals (C1-C4 andS1) were higher than those of the implanted animals. Thus the inventivedevice may reduce heart rate in subjects suffering from heart failure.Put another way, the inventive device provides may enhance theefficiency of the pulmonary system and therefore reduce the frequencywith which the heart must beat to satisfy the body's oxygen demands.

TABLE 6 Heart Rate (HR, beats per minute) Day 0 Wk. 1 Wk. 2 Wk. 3 Wk. 4Wk. 5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C1 131 147 127 127 117 123127 143 C2 146 192 165 138 156 149 C4 135 S1 143 131 124 123 125 125 130133 131 V1 121 149 151 110 132 137 94 106 91 V2 142 132 120 140 137 144126 135 V3 151 107 74 82 111 98 95 107 112 105 96 V4 187 159 118 130 139101 72 112 122 102 M.C. 139 ± 3 157 ± 18 139 ± 13 129 ± 5 136 ± 20 133 ±8  126 ± 1  136 ± 6 133 131 M.V. 150 ± 4 137 ± 1  116 ± 16 115 ± 3 130 ±6  120 ± 12 97 ± 11 115 ± 7 108 ± 9 105 99 ± 2

Table 7 presents the study's results relating to oxygen saturation inthe vena cava (VC_SO₂, %). The control animals and the implanted animalshad similar VC_SO₂ levels throughout the course of the study, althoughfor both groups the levels were lower than at baseline. It is expectedthat oxygen saturation in the vena cava is relatively low, because thevessel carries deoxygenated blood from the body to the heart.

TABLE 7 Oxygen Saturation in Vena Cava (VC_SO₂, %) Day 0 Wk. 1 Wk. 2 Wk.3 Wk. 4 Wk. 5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C1 90 85 84 85 8083 80 80 79 C2 80 81 75 77 75 78 C4 82 77 62 S1 V1 94 80 80 81 79 80 6880 80 80 79 80 V2 98 78 78 70 81 78 73 79 79 V3 75 74 75 74 71 75 74 7967 74 78 V4 73 73 72 67 76 71 76 79 73 74 75 M.C. 90 82 ± 1 81 ± 2 74 ±6 79 ± 1 79 ± 4 79 ± 1 80 79 M.V. 96 ± 1 76 ± 2 76 ± 2 75 ± 2 75 ± 3 76± 2 72 ± 1 77 ± 2 79 ± 0 73 ± 4 76 ± 2 78 ± 1

Table 8 presents the study's results relating to oxygen saturation inthe pulmonary artery (PA_SO₂, %). The PA_SO₂ values for the implantedanimals are somewhat higher than those for the control animals (e.g.,between about 5-10% higher), indicating that device 100 was patent andtransferring blood from the left atrium to the right atrium. It isexpected that oxygen saturation in the pulmonary artery is relativelylow, because the vessel carries deoxygenated blood from the heart to thelungs.

TABLE 8 Oxygen Saturation in Pulmonary Artery (PA_SO₂, %) Day 0 Wk. 1Wk. 2 Wk. 3 Wk. 4 Wk. 5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C1 84 8176 78 71 76 75 73 C2 64 77 67 70 69 70 C4 78 76 57 S1 V1 91 81 83 82 8185 82 83 84 83 80 80 V2 92 81 80 84 87 87 80 82 84 V3 77 79 84 79 76 8078 85 71 77 81 V4 76 80 84 75 78 76 83 83 78 77 77 M.C. 84 74 ± 5 76 ± 067 ± 5 71 ± 0 69 73 ± 2 75 73 M.V. 92 ± 0 79 ± 1 81 ± 1 84 ± 1 81 ± 3 82± 3 80 ± 1 81 ± 1 84 ± 0 77 ± 3 78 ± 1 79 ± 1

Table 9 presents the oxygen saturation in the left atrium (LA_SO₂, %).The LA_SO₂ values for the implanted animals are similar to those for thecontrol animals. Animals with LA_SO₂ values of less than 94% areconsidered to have low cardiac output.

TABLE 9 Oxygen Saturation in Left Atrium (LA_SO₂, %) Day 0 Wk. 1 Wk. 2Wk. 3 Wk. 4 Wk. 5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C1 100 96 97 9493 95 92 96 93 C2 96 97 98 99 96 95 C4 95 95 98 S1 V1 100 93 96 97 94 9697 97 97 97 96 96 V2 100 97 97 96 92 96 87 95 97 V3 96 93 97 96 93 97 9696 94 96 96 V4 95 96 96 97 97 97 99 98 97 98 98 M.C. 100 96 ± 0 96 ± 197 ± 1 96 ± 2 96 ± 1 94 ± 1 96 93 M.V. 100 ± 0 95 ± 1 96 ± 1 97 ± 0 95 ±1 96 ± 1 95 ± 3 97 ± 1 97 ± 0 96 ± 1 97 ± 1 97 ± 1

Table 10 presents the study's results pertaining to the left ventricleinternal diameter in diastole (LVIDd, cm), which also may be referred toin the art as left ventricular end-diastolic dimension (LVEDD or LVDD).It may be seen that the LVIDd for the control (C1-C4 and S1) andimplanted (V1-V4) animals were relatively similar, and does notsignificantly vary during weeks 1-12 of the study. This may beattributed to the relatively low pressures during implantation. It maybe expected that when the device 100 is implanted in a subject with highLAP, the LVIDd will decrease after implantation as a result of thesignificant reduction in LAP.

TABLE 10 Left Ventricle Internal Diameter in Diastole (LVIDd, cm) Day 0Wk. 1 Wk. 2 Wk. 3 Wk. 4 Wk. 5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C14.6 5.4 5.0 5.1 5.4 5.3 4.8 4.8 4.8 C2 4.0 4.1 4.4 4.4 4.0 4.0 3.8 C44.2 5.7 5.7 5.5 S1 4.3 4.7 4.9 5.0 4.7 5.0 5.0 5.0 4.4 5.0 V1 3.8 4.14.2 4.3 3.8 4.0 4.1 4.5 4.3 4.4 4.3 4.0 V2 5.3 4.5 4.5 5.4 5.0 4.9 5.04.9 5.0 V3 5.4 6.3 6.2 5.9 6.0 5.6 5.5 6.0 6.2 6.3 5.9 5.6 V4 4.4 4.94.7 4.3 4.0 3.9 4.1 4.1 4.1 4.2 4.4 4.1 M.C. 4.3 ± .1 5.0 ± .4 5.0 ± .35.0 ± .2 4.7 ± .4 4.7 ± .7 4.5 ± .4 4.9 ± .1 4.9 ± .1 4.4 5.0 M.V. 4.7 ±.4 5.0 ± .5 4.9 ± .4 5.0 ± .4 4.7 ± .5 4.6 ± .4 4.7 ± .3 4.9 ± .4 4.9 ±.5 5.0 ± .7 4.9 ± .5 4.6 ± .5

Table 11 presents the study's results pertaining to the left ventricleinternal diameter in systole (LVIDs, cm), which also may be referred toin the art as left ventricular end-systolic dimension (LVESD or LVSD).While the LVIDd discussed above with respect to Table 10 was similar forboth groups of animals, it may be seen here that for the controlanimals, the LVIDs increased from baseline in week one (e.g., from anaverage 3.5±0.2 at baseline to 4.2±0.3 at week one), and then increasedfurther and/or remained elevate. By comparison, the LVIDs for theimplanted animals increased slightly from baseline in week one (e.g.,from an average 4.0±0.2 at baseline to 4.2±0.4 at week one), but thendecreased relatively steadily over the course of the study (e.g., to3.5±0.4 at week twelve). This decrease reflects the remodeling of theleft ventricle over time that results from offloading blood flow fromthe left atrium back to the right atrium through the inventive device.

TABLE 11 Left Ventricle Internal Diameter in Systole (LVIDs, cm) Day 0Wk. 1 Wk. 2 Wk. 3 Wk. 4 Wk. 5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C13.8 4.7 4.4 4.5 4.9 4.9 4.4 4.4 4.4 C2 3.0 3.3 3.8 3.8 3.5 3.7 3.6 C43.5 4.8 5.0 5.1 S1 3.6 4.1 4.3 4.4 4.2 4.5 4.6 4.6 4.7 4.7 V1 3.6 3.53.5 3.6 3.2 3.3 3.4 3.7 3.6 3.6 3.5 3.2 V2 4.7 3.8 3.7 3.8 4.0 3.9 3.93.9 4.0 V3 4.6 5.3 5.2 4.9 4.9 4.6 4.5 4.9 5.0 5.0 4.7 4.4 V4 3.4 4.03.7 3.3 3.1 2.9 3.1 3.1 3.0 3.1 3.2 2.9 M.C. 3.5 ± .2 4.2 ± .3 4.3 ± .34.5 ± .3 4.2 ± .4 4.3 ± .6 4.2 ± .3 4.5 ± .1 4.5 ± .1 4.7 4.7 M.V. 4.0 ±.3 4.2 ± .4 4.0 ± .4 3.9 ± .4 3.8 ± .4 3.7 ± .4 3.7 ± .3 3.9 ± .4 3.9 ±.4 3.9 ± .6 3.8 ± .5 3.5 ± .4

Table 12 elaborates on the results of Table 11, and presents the changesin the left ventricle internal diameter in systole (ALVIDs, %). As canbe seen in Table 12, the control animals experienced an average increasein LVIDs of about 20-29% over the course of the study, while theimplanted animals experienced an average decrease in LVIDs of about0-9%. Thus, the inventive device may inhibit increases in the internaldiameter of the left ventricle in subjects suffering from heart disease,and indeed may reduce the internal diameter of the left ventricle insubjects suffering from heart disease, in some embodiments by up to 10%.

TABLE 12 Change in Left Ventricle Internal Diameter in Systole (ΔLVIDs,%) Day 0 Wk. 1 Wk. 2 Wk. 3 Wk. 4 Wk. 5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11Wk. 12 C1 +23 +15 +18 +28 +28 +16 +16 +16 C2 +11 +25 +27 +17 +23 +20 C4+37 +43 +46 S1 +13 +17 +22 +17 +24 +26 +27 +29 +28 V1 −1 −2 +1 −11 −8 −6+4 +1 +2 −2 −10 V2 −18 −21 −19 −14 −17 −17 −17 −14 V3 +17 +13 +8 +7 +1−2 +7 +10 +10 +2 −4 V4 +19 +9 −2 −9 −12 −7 −8 −9 −8 −6 −14 M.C. +21 ± 6+25 ± 6 +28 ± 6 +21 ± 4 25 ± 2 +20 ± 2 +21 ± 5 +22 ± 6 +29 +28 M.V.  +4± 9  +0 ± 8  −3 ± 6  −7 ± 5 −9 ± 4  −8 ± 3  −4 ± 6  −3 ± 5 +1 ± 5 −2 ± 2−9 ± 3

Table 13 presents the study's results pertaining to ejection fraction(EF, %). The EF of the control animals may be seen to declinesignificantly over the course of the study, while the EF of theimplanted animals increases significantly over the course of the study.For example, it may be seen that for the control animals, C1 experienceda decline in EF to about 45% of baseline; C2 to about 28% of baseline;C4 to about 47% of baseline; and S1 to about 41% of baseline. Bycomparison, for the implanted animals, V1 experienced an increase in EFto about 169% of baseline; V2 also to about 169% of baseline; V3 toabout 129% of baseline; and V4 to about 127% of baseline. The inventivedevice thus may not only inhibit decreases in EF of subjects sufferingfrom heart failure, but indeed may increase the EF of such subjectssignificantly, for example by 25-50%, or even 25-70% or more.

TABLE 13 Ejection Fraction (EF, %) Day 0 Wk. 1 Wk. 2 Wk. 3 Wk. 4 Wk. 5Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C1 35.5 28.9 26.8 23.5 21.0 18.317.8 16.4 16.0 C2 45.3 40.1 29.1 28.0 23.6 20.9 12.7 C4 34.3 32.4 25.216.2 S1 33.2 27.6 26.9 25.0 22.6 20.7 18.6 16.8 14.8 13.7 V1 24.5 27.336.1 36.6 35.9 36.0 35.7 35.7 35.6 37.7 37.8 41.4 V2 26.4 33.2 37.3 37.240.5 42.0 42.9 43.0 44.6 V3 32.6 33.6 33.3 34.5 37.2 37.2 37.9 38.2 38.941.0 41.8 41.9 V4 45.3 45.7 46.0 47.5 47.9 47.8 47.9 49.7 52.7 53.2 55.557.5 M.C. 37.1 ± 2.8 32.3 ± 2.8 27.0 ± .8  23.2 ± 2.5 22.4 ± .7  19.6 ±1.3 17.0 ± 2.3 17.5 ± 1.1 16.4 ± .4  14.8 13.7 M.V. 32.2 ± 4.7 34.9 ±3.9 38.2 ± 2.7 39.0 ± 2.9 40.4 ± 2.7 40.8 ± 2.7 41.1 ± 2.7 41.6 ± 3.142.9 ± 3.7 44.0 ± 4.7 45.0 ± 5.4 46.9 ± 5.3

Table 14 elaborates on the results presented in Table 14, and presentsthe change in ejection fraction. As can be seen in Table 14, the EF ofeach of the control animals decreased significantly relative tobaseline, e.g., by up to 72% for animal C2, while the EF for each of theimplanted animals increased significantly.

As noted above with respect to Table 10, the left ventricle internaldiameter in diastole (LVIDd) did not significantly change for theimplanted animals over the course of the study. Absent such a decreasein the LVIDd, an increase in the EF may be interpreted as an increase incardiac output. The inventive device thus may not only inhibit decreasesin cardiac output of subjects suffering from heart failure, but indeedmay increase the cardiac output of such subjects significantly.

TABLE 14 Change in Ejection Fraction (EF, %) Day 0 Wk. 1 Wk. 2 Wk. 3 Wk.4 Wk. 5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C1 −18 −24 −34 −41 −48−50 −54 −55 C2 −11 −36 −38 −48 −54 −72 C4 −6 −19 −53 S1 −17 −27 −25 −32−38 −44 −49 −55 −59 V1 +11 +47 +49 +46 +47 +46 +45 +45 +54 +54 +69 V2+26 +42 +41 +54 +59 +63 +63 +69 V3 +3 +2 +6 +14 +14 +16 +17 +19 +26 +28+29 V4 +1 +2 +5 +6 +6 +6 +10 +16 +18 +23 +27 M.C. −13 ± 3 −26 ± 4 −37 ±6  −40 ± 5  −51 ± 3  −53 ± 10 −49 ± 5  −52 ± 3  −55 −59 M.V. +10 ± 6 +23± 2 +25 ± 12 +30 ± 12 +32 ± 13 +33 ± 13 +34 ± 12 +38 ± 12 +32 ± 11 +35 ±10 +41 ± 14

Table 15 presents the study's results pertaining to fractionalshortening (FS, %). Similar to ejection fraction discussed above withrespect to Tables 13-14, the FS of each of the control animals may beseen in Table 15 to decline significantly over the course of the study.For example, animal C1 experienced a decline in FS to about 47% ofbaseline before death; animal C2 to about 24% of baseline; animal C4 toabout 46% of baseline; and animal S1 to about 39% of baseline. Incontrast, the FS of each of the implanted animals increasedsignificantly over the course of the study. For example, animal V1experienced an increase in FS to about 183% of baseline; animal V2 toabout 166% of baseline; animal V3 to about 132% of baseline; and animalV4 to about 127% of baseline. Thus, the inventive device not onlyinhibits decreases in fractional shortening for subjects suffering fromheart failure, but also may increase fractional shorteningsignificantly, e.g., by about 25-85% of baseline.

TABLE 15 Fractional Shortening (FS, %) Day 0 Wk. 1 Wk. 2 Wk. 3 Wk. 4 Wk.5 Wk. 6 Wk. 8 Wk. 9 Wk. 10 Wk. 11 Wk. 12 C1 17.0 13.7 12.5 10.9 9.7 8.48.0 7.5 8.0 C2 23.2 19.3 13.5 13.0 10.7 9.1 5.5 C4 16.2 15.5 11.8 7.4 S115.6 12.8 12.5 11.6 10.3 9.4 8.4 7.6 6.6 6.1 V1 10.9 12.6 17.1 17.5 16.916.9 16.9 17.0 16.9 18.1 17.6 20.0 V2 12.4 15.8 18.1 19.0 19.9 20.7 21.221.6 20.6 V3 15.7 16.4 16.2 16.7 18.3 18.2 18.5 18.8 19.3 20.5 20.8 20.8V4 22.4 22.6 22.9 23.7 23.7 23.6 23.8 24.9 26.7 27.1 28.8 28.4 M.C. 18.0± 1.8 15.3 ± 1.4 12.6 ± 0.4 10.7 ± 1.2 10.2 ± 0.3  8.7 ± 0.4  7.7 ± 1.2 8.0 ± 0.4  7.8 ± 0.2 6.6 6.1 M.V. 15.3 ± 2.5 16.8 ± 2.1 18.6 ± 1.5 19.2± 1.6 19.7 ± 1.5 19.8 ± 1.5 20.1 ± 1.5 20.6 ± 1.7 20.9 ± 2.1 21.9 ± 2.722.4 ± 3.3 23.1 ± 2.7

As the foregoing results illustrate, devices constructed and implantedaccording to the present invention may provide for significantlyimproved mortality rates in subjects suffering from heart failure. Inparticular, the devices may significantly enhance ejection fraction,fractional shortening, and/or cardiac output in subjects who wouldotherwise have significantly diminished cardiac function as a result ofexcessive left atrial and left ventricular pressures. For example,subjects may be classified under the New York Heart Association (NYHA)classification system as having Class II (Mild) heart failure, who haveslight limitation of physical activity and are comfortable at rest, butfor whom ordinary physical activity results in fatigue, palpitation, ordyspnea; Class III (Moderate) heart failure, who have marked limitationof physical activity, may be comfortable at rest, and may experiencefatigue, palpitation, or dyspnea if they engage in less than normalactivity; or as having Class IV (Severe) heart failure, who are unableto carry out any physical activity without discomfort, exhibit symptomsof cardiac insufficiency at rest, and have increased discomfort if theyundertake any physical activity. The present devices may significantlyincrease the cardiac output of such class III or class IV subjects,particularly those with low ejection fraction, enabling them to engagein significantly more physical activity than they otherwise could. Thepresent devices further may decrease pulmonary artery pressure insubjects with left heart failure, and additionally may reduce or inhibitpulmonary congestion in patients with pulmonary congestion resultingfrom such heart failure, for example by inhibiting episodes of acutepulmonary edema. Indeed, as the above-described Example illustrates, theinventive device may reduce LAP and PAP significantly relative to whatthose pressures would otherwise be; such pressure reductions may notonly provide immediate relief from acute symptoms, but further mayfacilitate cardiac remodeling over the weeks following implant and thusprovide for enhanced cardiac function. The devices may in someembodiments include means for measuring the various parameters ofinterest, e.g., means such as discussed above with respect to the animaltrials.

Delivery System

Referring to FIGS. 12A and 12B, apparatus 1200 is provided fordelivering devices of the present invention, e.g., device 100 of FIGS.1A to 1D, device 800 of FIGS. 8A to 8C, device 900 of FIG. 9, and/ordevices described in U.S. Patent Publication No. 2013/0030521 to Nitzan,assigned to the assignee of the present invention, the entire contentsof which are incorporated herein by reference. Apparatus 1200 mayinclude distal end 1202, catheter 1204, and proximal end 1206 havinghandle 1208. Distal end 1202 comprises components suitable for couplingapparatus 1200 to devices of the present invention, as described indetail below. Catheter 1204 comprises a biocompatible tube shaft ofsuitable size, e.g., approximately 14 Fr., and suitable length, e.g.,approximately 75-100 cm and preferably 85 cm. Proximal end 1206comprises handle 1208 that is configured to be manipulated, e.g., by ahuman hand, to transition components in distal end 1202 from an engagedposition shown in FIG. 12A to a disengaged position shown in FIG. 12B.Handle 1208 may be manipulated, for example, by moving finger grips 1210proximally from a locked position shown in FIG. 12A to an unlockedposition shown in FIG. 12B. In addition, handle 1208 may be manipulatedby moving finger grips 1210 distally from the locked position to theunlocked position so as to transition components in distal end 1202 fromthe disengaged position to the engaged position to load devices of thepresent invention.

FIGS. 13A and 13B illustrate distal end 1202 in the engaged position ofFIG. 12A and the disengaged position of FIG. 12B, respectively. Atdistal end 1202, apparatus 1200 may include latching legs 1212, 1214,and 1216 having hook portions 1218, 1220, and 1222, respectively.Latching legs 1212, 1214, and 1216 comprise a biocompatible materialsuch as a biocompatible metal or polymer, and are positionedlongitudinally and radially so as to firmly secure devices of thepresent invention for delivery. Hook portions 1218, 1220, and 1222extend outwardly from the distal end of latching legs 1212, 1214, and1216, respectively, and are configured to fit securely between strutsand rings of the devices of the present invention. Preferably, hookportions 1218, 1220, and 1222 hook outwardly away from center axis 1223of catheter 1204 in both the engaged and disengaged positions as shownin FIGS. 12A and 12B. Center axis 1223 is centered relative to catheter1204 on both a longitudinal and cross-sectional basis. By facingoutwardly from center axis 1223, hook portions 1218, 1220, and 1222 mayengage the inner surface of the device, e.g., within a lumen of a shunt.In one embodiment, hook portions 1218, 1220, and 1222 hook generallyperpendicularly away from center axis 1223 from a radial perspective. Aswill be readily understood by one of ordinary skill in the art, whilethree latching legs are illustrated, more or fewer latching legs may beused without departing from the scope of the present invention. Forexample, one, two, four, five, six, or more latching legs may be used.Catheter 1204 may include catheter end 1224 which may have a largerdiameter than the remaining shaft of catheter 1204. Catheter end 1224comprises a biocompatible material such as a biocompatible metal orpolymer, and may be the same or different material than the remainingshaft of catheter 1204. Components at distal end 1202, such as latchinglegs 1212, 1214, and 1216, may be at least partially disposed withincatheter end 1224.

Referring now to FIGS. 14A to 14D, the inner components at distal end1202 of apparatus 1200 are illustrated. FIGS. 14A and 14B respectivelyillustrate distal end 1202 in the engaged position of FIGS. 12A and 13Aand the disengaged position of FIGS. 12B and 13B. As shown in FIG. 14A,catheter 1204 and catheter end 1224 comprise lumens 1226 and 1228,respectively, for housing the inner components. Latching legs 1212 and1214 share common ramp portion 1230 having inner section 1232 and outersection 1234 while latching leg 1216 has separate ramp portion 1236having inner section 1238 and outer section 1240. Inner sections 1232and 1238 are angled so as to be positioned closer to the central axis ofcatheter 1204 and catheter end 1224 relative to the positions of outersections 1234 and 1240. Latching legs may also include jogs andprotrusions. For example, latching leg 1216 illustratively includesprotrusion 1242 proximal to ramp portion 1236, and jog 1244 between hookportion 1222 and ramp portion 1236. Protrusion 1242 is configured tocontact the distal surface of annular member 1248 to maintain suitablepositioning of latching leg 1216. Jog 1244 is shaped to prevent releasering 1246 from moving too distally.

Release ring 1246 is coupled to latching legs 1212, 1214, and 1216. Forexample, latching legs 1212, 1214, and 1216 may be partially disposedwithin release ring 1246 as illustrated in FIGS. 14A to 14D. Releasering 1246 is moveable within catheter end 1224. Release ring 1246 may belocated in a first position, e.g., an engaged position, where releasering 1246 contacts inner sections 1232 and 1238 of ramp portions 1230and 1236 such that latching legs 1212, 1214, and 1216 extend radiallyoutward as shown in FIGS. 14A and 14C. Release ring 1246 may be moved toa second position, e.g., a disengaged position, where release ring 1246contacts outer sections 1234 and 1240 of ramp portions 1230 and 1236such that latching legs 1212, 1214, and 1216 move radially inward asshown in FIGS. 14B and 14D. In one embodiment, release ring 1246 isconfigured to move from the second position to the first position toload a device of the present invention and to move from the firstposition to the second position to release the device.

Annular member 1248 may be partially disposed in the proximal end ofcatheter end 1224 and configured to couple catheter end 1224 to catheter1204 via a suitable coupling mechanism, e.g., teeth 1250, ribs. Annularmember 1248 includes lumen 1252 sized to accept pull chord 1254therethrough.

Pull chord 1254 is coupled to release ring 1246 and actuation of pullchord 1254 moves release ring 1246 from the first position shown in FIG.14A to the second position shown in FIG. 14B, and vice versa. In apreferred embodiment, pull chord 1254 is coupled to handle 1208 suchthat pull chord 1254 is actuated by moving finger grips 1210 from alocked position shown in FIG. 12A to an unlocked position shown in FIG.12B, and vice versa.

Pull chord 1254 may be coupled to release ring 1246 via release ringbase 1256. In this embodiment, release ring base 1256 is directlycoupled to release ring 1246 and pull chord 1254 such that actuation ofpull chord 1254 moves release ring base 1256 to move release ring 1246from the first position the second position, and vice versa.

Spring 1258 may be coupled to the proximal surface of release ring base1256 and the distal surface of annular member 1248 such that releasering base 1256 and annular member 1248 maintain spring 1258therebetween. Spring 1258 is configured to bias release ring 1246towards a particular position such as towards the first position asshown in FIG. 14A.

FIGS. 14A and 14C illustrate the components at distal end 1202 in anengaged position, where FIG. 14C omits catheter end 1224 for clarity. Aspull chord 1254 is actuated, e.g., via handle 1208, release ring 1246 ismoved, e.g., via release ring base 1256, from the engaged position tothe disengaged position shown in FIGS. 14B and 14D, where FIG. 14D omitscatheter end 1224 for clarity. Release ring 1246 slides along rampportions 1230 and 1236 from inner sections 1232 and 1238 to outersections 1234 and 1240 such that latching legs 1212, 1214, and 1216 movefrom being extended radially outward to being positioned radiallyinward. As release ring 1246 moves from the engaged position to thedisengaged position, spring 1258 is compressed and as release ring 1246moves from the disengaged position to the engaged position, spring 1258is decompressed.

FIG. 15A illustrates the components at distal end 1202 of apparatus 1200engaged to an exemplary device of the present invention and FIG. 15Billustrates the components disengaged from the exemplary device. Device1500 includes rings 1502 and struts 1504 and may be constructed similarto device 100 of FIGS. 1A to 1D, device 800 of FIGS. 8A to 8C, device900 of FIG. 9, and/or devices described in U.S. Patent Publication No.2013/0030521 to Nitzan. As shown in FIG. 15A, latching legs 1212, 1214,and 1216 are sized, shaped, angled, and spaced apart from one another soas to engage device 1500 in openings between rings 1502 and struts 1504when device 1500 is in a contracted, delivery state. Hook portions 1218,1220, and 1222 also are sized, shaped, and angled to fit between rings1502 and struts 1504 and hook portions 1218, 1220, 1222 hook outwardlyaway from the center axis at the distal end of the delivery apparatussuch that hook portions 1218, 1220, 1222 are disposed in the lumen ofdevice 1500 in the disengaged position of FIG. 15B and engage at theinner surface of device 1500. As shown in FIG. 15B, latching legs 1212,1214, and 1216 are configured to move radially inward a sufficientdistance to decouple hook portions 1218, 1220, and 1222 from device 1500in the disengaged position, thereby releasing device 1500 forimplantation.

Exemplary method 1600 of delivering device 100 illustrated in FIGS.1A-1D to reduce left atrial pressure in a subject, for example, a humanhaving CHF, using apparatus 1200 illustrated in FIGS. 12A-12B will nowbe described with reference to FIG. 16. Some of the steps of method 1600may be further elaborated by referring to FIGS. 17A-17Q.

First, a device and apparatus for delivering the device are provided(step 1601). The device may be an hourglass-shaped device having aplurality of sinusoidal rings connected by longitudinally extendingstruts that define first and second flared end regions and a neckdisposed therebetween, as well as an optional tissue valve coupled tothe first flared end region. Such a device may be provided, for example,using method 300 described above with respect to FIGS. 3A-3E. Thedelivery apparatus may be apparatus 1200 illustrated in FIGS. 12A-12B.

Then, the device is collapsed radially to a contracted, delivery stateand coupled to the delivery apparatus (step 1602). For example, asillustrated in FIGS. 17A-17C, device 100 may be loaded into loading tube1700 by first placing device 100 within wide diameter end 1702 ofloading tube 1700 as shown in FIG. 17A. Then, using loading tool 1702,device 100 is crimped down within loading tube 1700. Loading tool 1704includes thin leg end 1706 having two thin legs and wide leg end 1708having two wide legs. Device 100 may be pushed into loading tube 1700first by wide leg end 1708 as illustrated in FIG. 17B and then pushedfurther into loading tube 1700 by thin leg end 1706 as illustrated inFIG. 17C.

In FIG. 17D, device 100 is disposed within thin diameter end 1710 ofloading tube 1700. Thin diameter end 1710 has a suitable internaldiameter for contracting the device, e.g., approximately 14 Fr. Loadingtube 1700 includes tapered section 1712 between wide diameter end 1702and thin diameter end 1710. Tapered section 1712 facilitates radialcompression of device 100 into thin diameter end 1710. Loading tube 1700is coupled to loading cartridge 1714 via coupling section 1716 having asuitable coupling mechanism, e.g., threads, ribs. Loading cartridge 1714may be transparent and has a suitable internal diameter, e.g.,approximately 14 Fr.

Referring to FIG. 17E, device 100 is pushed into loading cartridge 1714using pusher 1718. Pusher 1718 has a suitable diameter, e.g.,approximately 14 Fr., and may have a “star”-shaped end (not shown).Loading cartridge 1714 is disconnected from loading tube 1700 andconnected to hemostatis valve section 1720, which may be a Tuohy Borstvalve, as shown in FIG. 17F. Valve section 1720 includes knob 1722 andY-connector 1724. Distal end 1202 of apparatus 1200 is inserted throughknob 1722 of valve section 1720. Knob 1722 and Y-connector 1724 areadjusted to permit movement of apparatus 1200 while maintaining a sealto prevent fluid leakage, e.g., air leakage, blood leakage. The stepsshown in FIGS. 17A-17F may be performed while device 100 is immersed inan anticoagulant such as heparinized saline.

FIGS. 17G and 17H illustrate coupling device 100 to apparatus 1200 atdistal end 1202. Distal end 1202 is advanced within loading cartridge1714 toward device 100. The components of distal end 1202 may be in thedisengaged position as illustrated in FIG. 17G. For example, the releasering at distal end 1202 may contact an outer section of the rampportions of the latching legs such that the latching legs are disposedradially inward. Next, distal end 1202 is moved longitudinally towarddevice 100 and rotated to align the latching legs with suitable portionsof device 100, e.g., at openings between struts and rings of device 100.Once suitable position is achieved, the components of distal end 1202may move to the engaged position as illustrated in FIG. 17H. Forexample, the release ring may be moved via a pull chord and handle suchthat the release ring contacts an inner section of the ramp portions ofthe latching legs so the latching legs extend radially outward. Aclinician may verify that device 100 is engaged to apparatus 1200 byslowing advancing and retracting apparatus 1200 a distance, e.g.,approximately 5 mm, while device 100 remains in loading cartridge 1714.In addition, a clinician may verify that apparatus 1200 is capable ofdisengaging from device 100 within loading cartridge 1714 by pressinghandle to cause the components at distal end 1202 to disengage and thenmoving distal end 1202 away from device 100. After such verification,the clinician may reengage apparatus 1200 to device 100. Preferably,device 100 is loaded into loading cartridge 1714 shortly beforeimplantation, so as to avoid unnecessarily compressing device 100 orre-setting of the closed shape of leaflets 132, which may interfere withlater deployment or operation of the device.

Referring back to FIG. 16, the device then is implanted, first byidentifying the fossa ovalis of the heart septum, across which device100 is to be deployed (step 1603). Specifically, a BROCKENBROUGH needlemay be percutaneously introduced into the right atrium via the subject'svenous vasculature, for example, via the femoral artery. Then, underfluoroscopic or echocardiographic visualization, the needle is pressedagainst the fossa ovalis, at a pressure insufficient to puncture thefossa ovalis. As illustrated in FIG. 5C, the pressure from needle 530causes “tenting” of fossa ovalis 541, i.e., causes the fossa ovalis tostretch into the left atrium. Other portions of atrial septum 540 arethick and muscular, and so do not stretch to the same extent as thefossa ovalis. Thus, by visualizing the extent to which differentportions of the atrial septum 540 tents under pressure from needle 530,fossa ovalis 541 may be identified, and in particular the centralportion of fossa ovalis 541 may be located.

Referring again to FIG. 16, the fossa ovalis (particularly its centralregion) may be punctured with the BROCKENBROUGH needle, and a guidewiremay be inserted through the puncture by threading the guidewire throughthe needle and then removing the needle (step 1604). The puncturethrough the fossa ovalis then may be expanded by advancing a dilatorover the guidewire. Alternatively, a dilator may be advanced over theBROCKENBROUGH needle, without the need for a guidewire. The dilator isused to further dilate the puncture and a sheath then is advanced overthe dilator and through the fossa ovalis; the dilator and guidewire orneedle then are removed (step 1605). The sheath, which may be 14 Fr., isthen flushed.

Distal end 1202 of apparatus 1200, with device 100 coupled thereto in acontracted, delivery state, then is advanced into the sheath (step1606). For example, the delivery system may be flushed, e.g., via fluidconnected to fluid tube 1730, and then loading cartridge 1714 may becoupled to sheath 1726, e.g., via port 1728, as illustrated in FIG. 17I.The clinician should verify that loading cartridge contains no airtherein. Next, while holding sheath 1726 in place, loading cartridge1714 is advanced distally within port 1728 as illustrated in FIG. 17G.The device and delivery apparatus are advanced distally in sheath 1726until proximal end 1206 of apparatus 1200 is a predetermined distance X,e.g., approximately 1 cm, from knob 1722 as illustrated in FIG. 17K. Thedelivery system again may be flushed, e.g., via fluid connected to fluidtube 1730. The engagement of the latching legs of apparatus 1200 withdevice 100 permit movement of device 100 longitudinally forward andlongitudinally backward through sheath 1726.

Then, under fluoroscopic or echocardiographic visualization, sheath 1726may be repositioned such that the distal tip of sheath 1726 is disposeda predetermined distance, e.g., approximately 1-2 cm, distal to thefossa ovalis towards the left atrium. Next, device 100 and apparatus1200 are advanced distally such that the device is partially advancedout of the sheath so the second flared end of the device protrudes outof the sheath and into the left atrium, and expands to its deployedstate (step 1607). For example, device 100 and apparatus 1200 may beadvanced distally until the handle at proximal end 1206 contacts knob1722 as shown in FIG. 17L. Such advancement causes device 100 topartially protrude out of sheath 1726 and into left atrium LA, whichcauses the second flared end region to expand in the left atrium LA, asshown in FIG. 17M. The neck of device 100 is configured to self-positiondevice 100 within the distal end of sheath 1726 when device 100 ispartially deployed. Device 100 may be advanced across the atrial septumAS such that the angle θ between center axis 1728 of device 100, sheath1726, apparatus 1200, and/or catheter 1204 and the outer surface of theatrial septum at the left atrial side below device 100 is generallyperpendicular, e.g., between about 80 and about 100 degrees, betweenabout 85 and about 95 degrees, or about 90 degrees, as shown in FIG.17M. Alternatively, device 100 may be positioned across the atrialseptum AS, e.g., across a puncture through the fossa ovalis, at anon-perpendicular angle between center axis 1728 and the outer wall ofthe atrial septum at the left atrial side below device 100. For example,the angle θ′ may be substantially greater than 90 degrees as shown inFIG. 17N. Such an angle may be appropriate when device 100, sheath 1726,apparatus 1200, and/or catheter 1204 are advanced toward the atrialseptum transapically or through the inferior vena cava. Exemplary anglesθ′ between center axis 1728 and the outer surface of the atrial septumbelow device 100 include between about 110 and about 170 degrees,between about 120 and about 160 degrees, between about 130 and about 150degrees about 120 degrees, about 125 degrees, about 130 degrees, about135 degrees, about 140 degrees, about 145 degrees, about 150 degrees,about 155 degrees, about 160 degrees, about 165 degrees, and about 170degrees.

As another example, the angle θ″ may be substantially less than 90degrees as shown in FIG. 17O. Such an angle may be appropriate whendevice 100, sheath 1726, apparatus 1200, and/or catheter 1204 areadvanced toward the atrial septum through the superior vena cava.Exemplary angles θ″ between center axis 1728 and the outer surface ofthe atrial septum at the left atrial side below device 100 includebetween about 10 and about 70 degrees, between about 20 and about 60degrees, between about 30 and about 50 degrees, about 10 degrees, about15 degrees, about 20 degrees, about 25 degrees, about 30 degrees, about35 degrees, about 40 degrees, about 45 degrees, about 50 degrees, about55 degrees, about 60 degrees, about 65 degrees, and about 70 degrees.

An hourglass shape may aid in non-perpendicular deployment because theflared ends of the device engage the atrial septum, even when positionedat an angle relative to the central axis of the puncture through theatrial septum.

Next, under fluoroscopic or echocardiographic visualization, it isverified that the second flared end of the device protrudes from sheath1726 and then knob 1722 is used to lock the delivery system in place.Sheath 1726 is pulled proximally to perform “back tenting,” causing thesecond flared end region of device 100 to engage the left side of theatrial septum AS as shown in FIG. 17M. Such a feature may preventaccidentally deploying the entire device in the left atrium LA and mayassist in positioning the device when advanced at non-perpendicularangles as described in FIGS. 17N and 17O.

Using fluoroscopic or echocardiographic visualization, the cliniciannext verifies that the device is positioned across the fossa ovalis. Theclinician then reduces the pulling force of the sheath and allows thefossa ovalis to straighten. Then, while holding sheath 1726 in place,knob 1722 is released and the components at distal end 1202 of apparatus1200 are moved from an engaged position to a disengaged position, e.g.,by actuating handle 1208 as shown in FIG. 17P. Then, apparatus 1200 ispulled proximally a predetermined distance, e.g., approximately 5-6 cm.

The device then may be fully deployed by pulling the sheath proximallycausing the second flared end region to flank the left side of theatrial septum and the neck of the device to lodge in the puncturethrough the fossa ovalis, and allowing expansion of the first flared endof the device into the right atrium as shown in FIG. 17Q (step 1608).Any remaining components of the delivery system then may be removed,e.g., sheath and distal end of delivery apparatus (step 1609). Oncepositioned in the fossa ovalis, the device shunts blood from the leftatrium to the right atrium when the left atrial pressure exceeds theright atrial pressure (step 1610), thus facilitating treatment and/orthe amelioration of symptoms associated with CHF.

It should be noted that the inventive devices also may be used withpatients having disorders other than heart failure. For example, in oneembodiment the device may be implanted in a subject suffering frommyocardial infarction, for example in the period immediately followingmyocardial infarction (e.g., within a few days of the event, or withintwo weeks of the event, or even within six months of the event). Duringsuch a period, the heart remodels to compensate for reduced myocardialfunction. For some subjects suffering from severe myocardial infarction,such remodeling may cause the function of the left ventricle tosignificantly deteriorate, which may lead to development of heartfailure. Implanting an inventive device during the period immediatelyfollowing myocardial infarction may inhibit such deterioration in theleft ventricle by reducing LAP and LVEDP during the remodeling period.For example, in the above-described Example, heart failure was inducedin the sheep by injecting microspheres that block the coronary arteryand induce myocardial infarction. Following the myocardial infarction,the sheep developed heart failure. As can be seen in the various resultsfor the implanted animals, implanting the inventive device even a weekfollowing the myocardial infarction inhibited degradation of the heartand yielded significantly improved mortality rates and cardiacfunctioning both immediately and over time as the subjects' heartsremodeled. As such, it is believed that implanting an inventive devicefor even a few weeks or months following myocardial infarction mayprovide significant benefits to the subject as their heart remodels. Thedevice optionally then may be removed.

While various illustrative embodiments of the invention are describedabove, it will be apparent to one skilled in the art that variouschanges and modifications may be made herein without departing from theinvention. It will further be appreciated that the devices describedherein may be implanted in other positions in the heart. For example,device 100 illustrated in FIGS. 1A-1D may be implanted in an orientationopposite to that shown in FIG. 2B, so as to shunt blood from the rightatrium to the left atrium, thus decreasing right atrial pressure; such afeature may be useful for treating a high right atrial pressure thatoccurs in pulmonary hypertension. Similarly, device 100 may be implantedacross the ventricular septum, in an orientation suitable to shunt bloodfrom the left ventricle to the right ventricle, or in an orientationsuitable to shunt blood from the right ventricle to the left ventricle.The appended claims are intended to cover all such changes andmodifications that fall within the true spirit and scope of theinvention.

What is claimed:
 1. A method of implanting an atrial shunt having firstand second flared end regions within a subject with heart pathology, thesubject having a heart with an atrial septum having a fossa ovalistherein, the method comprising: collapsing the atrial shunt to acontracted delivery state; coupling the first flared end region of thecollapsed atrial shunt to a distal end of a delivery apparatus;advancing the collapsed atrial shunt and the delivery apparatus througha sheath positioned across a puncture through the fossa ovalis, thecollapsed atrial shunt and the delivery apparatus configured to movelongitudinally forward and longitudinally backward through the sheath;positioning the collapsed atrial shunt across the puncture through thefossa ovalis at a non-perpendicular angle between a center axis of thedelivery apparatus and an outer wall of the atrial septum such that thesecond flared end region is disposed in a left atrium in an expandedstate; and deploying the atrial shunt at the atrial septum such that aneck region of the atrial shunt is positioned in the puncture, the firstflared end region of the atrial shunt is disposed in a right atrium inan expanded state, and the second flared end region is disposed in theleft atrium in the expanded state.
 2. The method of claim 1, whereincoupling the first flared end region of the collapsed atrial shunt tothe distal end of the delivery apparatus comprises coupling a hookportion of the delivery apparatus to the first flared end region of thecollapsed atrial shunt.
 3. The method of claim 2, wherein coupling thehook portion of the delivery apparatus to the first flared end region ofthe collapsed atrial shunt comprises transitioning the hook portion froma disengaged position to an engaged position when the first flared endregion of the collapsed atrial shunt is in a desired positioned relativeto the hook portion of the delivery apparatus.
 4. The method of claim 3,wherein transitioning the hook portion from the disengaged position tothe engaged position comprises moving a ring coupled to one or morelatching legs of the hook portion between a first position, where thering contacts a first section of a ramp portion of the hook portion suchthat the one or more latching legs move radially inward, and a secondposition, where the ring contacts a second section of the ramp portionsuch that the one or more latching legs extend radially outward tocouple the hook portion to the atrial shunt.
 5. The method of claim 4,wherein deploying the atrial shunt at the atrial septum comprises movingthe ring from the first position to the second position to decouple thehook portion from the atrial shunt.
 6. The method of claim 1, whereinpositioning the collapsed atrial shunt across the puncture through thefossa ovalis at the non-perpendicular angle comprises locking thedelivery apparatus in place and retracting the sheath to engage thesecond flared end region of the atrial shunt with the atrial septum atthe non-perpendicular angle.
 7. The method of claim 6, wherein theatrial shunt comprises an hourglass shape to aid engagement of thesecond flared end region of the atrial shunt with the atrial septum atthe non-perpendicular angle.
 8. The method of claim 6, wherein lockingthe delivery apparatus in place comprises actuating a knob of a handlecoupled to a proximal end of the delivery apparatus.
 9. The method ofclaim 1, wherein the non-perpendicular angle between the center axis ofthe delivery apparatus and the outer wall of the atrial septum isbetween 110 and 170 degrees.
 10. The method of claim 9, whereinadvancing the collapsed atrial shunt and the delivery apparatus throughthe sheath comprises advancing the collapsed atrial shunt and thedelivery apparatus toward the atrial septum transapically.
 11. Themethod of claim 9, wherein advancing the collapsed atrial shunt and thedelivery apparatus through the sheath comprises advancing the collapsedatrial shunt and the delivery apparatus toward the atrial septum throughan inferior vena cava.
 12. The method of claim 1, wherein thenon-perpendicular angle between the center axis of the deliveryapparatus and the outer wall of the atrial septum is between 10 and 70degrees.
 13. The method of claim 12, wherein advancing the collapsedatrial shunt and the delivery apparatus through the sheath comprisesadvancing the collapsed atrial shunt and the delivery apparatus towardthe atrial septum through a superior vena cava.
 14. The method of claim1, wherein deploying the atrial shunt at the atrial septum comprisesadvancing the collapsed atrial shunt and the delivery apparatus relativeto the sheath until the second flared end region of the atrial shuntprotrudes beyond the sheath and transitions from the contracted deliverystate to the expanded state within the left atrium.
 15. The method ofclaim 14, further comprising verifying that the second flared end regionis disposed in the left atrium in the expanded state via fluoroscopic orechocardiographic visualization.
 16. The method of claim 14, whereindeploying the atrial shunt at the atrial septum further comprisespulling the sheath proximally relative to the atrial septum causing thesecond flared end region of the atrial shunt to flank a left side of theatrial septum and a neck region of the atrial shunt to lodge in thepuncture through the fossa ovalis, and allowing the first flared endregion to transition from the contracted delivery state to the expandedstate within the right atrium.
 17. The method of claim 1, furthercomprising advancing a needle against the fossa ovalis to create thepuncture through the fossa ovalis.
 18. The method of claim 1, furthercomprising: inserting a guidewire through the puncture through the fossaovalis; advancing a dilator over the guidewire to dilate the puncture;and advancing the sheath over the dilator to position the sheath acrossthe puncture through the fossa ovalis.
 19. The method of claim 1,further comprising flushing the atrial shunt and the delivery apparatuswithin the sheath.
 20. The method of claim 1, further comprisingshunting blood across the atrial septum through the atrial shuntresponsive to a pressure differential across the atrial septum tothereby treat the heart pathology.
 21. The method of claim 1, furthercomprising removing the sheath and the delivery apparatus, such that theatrial shunt aligns itself within the puncture through the fossa ovalis.